Hpv vaccines will they prevent cervical cancer - Free Essay Example

HPV Vaccines: Will They Prevent Cervical cancer Introduction Human papilloma viruses (HPV) belong to the papillomaviridae family, they are double stranded DNA viruses. HPV is the most common sexually transmitted infection (STI) in the world (Urman et al. 2008). HPV is strongly associated with cervical cancer; more than 99% what are the other causes/factors please of cervical cancer cases are positive for HPV DNA and indeed, cervical cancer is the second most common malignancy in the world (Wang et al. 2007). In developed countries the incidence of cervical cancer has been reduced significantly by the introduction of a cervical screening programme. In developing countries where 83% of mortalities due to cervical cancer occur, there are no such programmes (Parkin et al. 2006). Can the introduction of a vaccine against HPV further reduce globally the incidence of cervical cancer? Many diseases caused by viruses are controlled in the developed world by ongoing successful vaccination programmes; Polio, Measles, Mumps and Rubella are a few examples. Smallpox caused by Variola virus was eradicated in 1979 through a successful worldwide vaccination programme. The factors that affect the Polio and MMR vaccine programmes success and those that affected the successful smallpox programme may also be contributory to the success of the HPV vaccination program. Vaccination of HPV is complex and multi factorial. This investigation studies a number of factors including: * Vaccine efficacy * Vaccine Cost/affordability/practicality of administration * Production and Distribution * Government backing and financial commitment * Other support organisations such as the WHO, UNICEF, Gates Foundation, * Social factors * Media effects * Public awareness * Safety, and perceived fears Currently two prophylactic vaccines against HPV types 16 and 18, the most prevalent causes of HPV have been approved by the food and drug administration (FDA). Many developed countries have already introduced vaccination programmes using one of these vaccines. Can the vaccines and programme prevent cervical cancer? In order to effectively understand the implication of such a vaccination programme we must first fully examine the causative agent (HPV) and the consequential potential diseases including the biology, history and prevalence. Human Papillomavirus Approximately 200 types of HPV are identified of which around 40 infect the genital tract (McCance 2004). The majority of HPV types cause no symptoms, some types can cause warts and a minority may lead to cancer. Genital HPVs are transmitted via sexual contact, mainly intercourse, with an infected individual, and the risk of developing an HPV infection generally increases with the number of sexual partners, the sexual history of that partner or the introduction of a new sexual partner. Studies have shown that at least one type of HPV infection occurs soon after sexual debut, with around 30% of women infected with at least one high risk type within two years (Winer et al 2003; Winer et al 2008). HPVs are classified as either high risk or low risk, on the basis of association with cervical cancer. There are 15 types classified as high risk and three as probable high risk. High risk types include 16,18,31,33,35,39,,45,51,52,56,58,59,68,73,probable high risk types include 26,53,66 Low risk types include 6,11,40,42,43,54,61,70,72,81 and CP6108. More than 99% of cervical cancers are associated with HPV, of these 70% are associated with HPV type 16 and 18, with HPV 16 causing 50% and HPV 18 causing more than 15% in Europe (Smith et al..2007). HPV 16 is thus the single, most common high risk HPV. Interestingly HPV types 16 and 18 also cause 80% of anal cancer and 30% of vaginal and why the difference in % oper area research needed here.vulvar cancer and are associated with cancers of the, oropharynx and some rare cancers of the head and neck. (add reference form cervical cancer burden worldwide paper) The majority of HPV infections are asymptomatic, self limiting, and transient, with 70% of new HPV high risk type infections cleared within one year (with the median duration of an infection at 8 months) and 90% within two years (Ho et al 1998). The transient infection usually causes no clinical problems. A small proportion of high risk type infections persist due to host immune evasion, an evasion that results not only from restriction of HPVs to sites that are relatively inaccessible to host defences but also due to several mechanisms of preventing immune response what are these mechanisms please (a sk Dick if this is what he means . This persistence is the most important factor in the development of pre cancerous and cancerous lesions. The time span between infection by HPV and the development of pre cancerous lesions or cervical carcinoma varies from one to ten years (Moscicki et al 2006) and up to 20 years from other sources. HPV show little evidence of dramatic adaptability with phylogenic studies suggesting that the biology of HPVs has remained the same for over 200,000 years (Halpren et al 2000). While HPVs show historically the influence of point mutations, inserts, deletions and duplications, the predominant pattern of mutation within a given type is point mutation, with large scale rearrangements within the most conserved genes of HPVs such as L1 being rare (Myers et al 1996). Intra patient variation within HPV types is uncommon due to their low mutation rate. This low mutation rate is directly linked to the HPV replication strategy that requires host cell machinery, which has stringent proof reading mechanisms that avoid the incorporation of errors, conferring slow mutagenesis. All HPVs exhibit extreme specificity for infection of epithelial cells and do not infect or express their gene products in the underlying dermis. Although the mechanism of infection is not fully understood, the HPV epitheliotrophy resides for the most part in the interaction of specific transcription factors with the viral regulatory region known as the long control region (LCR). Infection with HPV can result in hyperproliferation of the host cell, and with certain high risk HPV types it may lead to transformation and immortalization. This is because high risk HPVs express two or more protein products (E6, E7 and E5) that transiently disrupt the cell cycle and stimulate cell division, knocking out at the same time the cellular mechanisms for growth inhibition. For a productive infection, HPVs require terminally differentiated cells. This HPV biology feature has impeded studies on the full reproduction life cycle because of the lack of highly efficient models of epithelial terminal di fferentiation in vitro. Most of the different stages in the HPV life cycle have been established using genetic engineering and molecular biology strategies. The dsDNA of HPV exists in a non enveloped icosahedral shaped virion 52-55 nm in diameter. The dsDNA genome is circularised and around 8000base pairs in length (Fig1). The genome encodes eight proteins, six early E1, E2, E4, E5, E6, E7, and two late structural proteins L1 and L2 and the previously mentioned noncoding LCR. Fig 1 HPV type 16 Genome structure, gene and functional domain location https://www.dnachip-link.com/Eng/library/HPV.aspusg 15/11/20009 Fig 1 shows the dsDNA genome of HPV type 16, and the location of the early and late genes along with the LCR that contains the origin of replication. An initial infection requires the access of infectious particles to the basal layer of the epithelium. Some HPVs require a break in the stratified epithelium to achieve this. Such breaks are not necessarily obvious and may occur under conditions where the skin is exposed to water or abraded, or subjected to an environment where micro traumas may occur such as possibly in aswiming pool or ect (must put an example)(in fig 2 shows as a cut). Following infection and uncoating it is thought that the virus maintains its genome as an episome in low copy numbers within basal cells of the epithelium. Although the pattern of gene expression in these cells is not well understood, it is generally thought that viral proteins E1 and E2 are expressed to maintain the viral DNA episome (Wilson et al.2002) and possibly to facilitate the segregation of genomes during cell division (You et all.2004). It is not known whether viral transformation proteins E6 and E7 are also expressed in the basal layer, but it does appear that initial infection is followed by a proliferative phase that results in the increase in the number of basal cells harbouring viral episomes. In normal uninfected epithelium, basal cells leave the cell cycle soon after migration into the superbasal cell layers where they undergo a process of terminal differentiation. During infection E6 and E7 are expressed in these cells stopping normal differentiation (Sherman et all.1997). E6 and E7 are believed to work together to achieve this and in lesions caused by high risk HPV types. During a natural infection the ability of E7 to stimulate S-phase progression is limited to a subset of differentiated cells with low levels of p21/p27, or which express high enough levels of E7 to overcome the block in S-phase entry. The viral E6 protein is thought to prevent apoptosis in response to unscheduled S-phase entry brought on by E7. The association of E6 with p53 and the inactivation of p53 mediated growth suppression and apoptosis is well documented, E6 may also associate with other pro-apoptotic proteins including bak (Thomas and Banks,1998) and bax (Li and Dou,2000). E6 is thus considered a predisposing factor in the development of HPV associated cancers, allowing the accumulation of chance errors in host DNA to go unchecked. Furthermore the E6 protein of high risk HPVs can stimulate cell proliferation independently of E7 via a c-terminal PDZ ligand binding domain. E6 PDZ is enough to mediate superbasal cell proliferation and may contribute to the formation of metastatic tumours by disrupting normal cell adhesion (Nguyen et al.2003) Amplification of the viral genome and the ability to package these genomes into infectious particles is essential for the production of infectious virions. For most HPV types this occurs in the mid or upper epithelial layers following an increase in activity of the late promoter. The late promoter gene is located within the E7 open reading frame, and the upregulation of the late promoter is thought to lead to increased expression of proteins involved in viral DNA replication, without directly affecting the expression of E6 or E7 necessary for S-phase entry. The amplification of the viral genome begins in a subset of cells in the proliferative compartment and requires the expression of all viral early gene products, these include E4 and E5 whose role in replication is not yet clearly understood. Binding of E2 to the HPV upstream regulator region is essential for viral DNA replication that is dependent on the differentiated state of epithelial cells. E2 recruits the E1 DNA helicase to the viral origin of replication. Throughout the virus life cycle, the relative levels of viral proteins are controlled by promoter usage and by differential splice site selection, with an increase in E1 and E2 allowing an increase in viral copy numbers in the upper epithelial layers. Current models suggest that a small increase in promoter activation during differentiation may lead to an increase in the level of E1 and E2 and a subsequent increase in genome copy number. The newly replicated genome could then serve as a further template for expression of E1 and E2, facilitating the amplification of viral genome and in turn further expression of E1 and E2 replication proteins. Viral DNA remains latent (not integrated) in basal cells of benign lesions. Replication occurs in the differentiating cells where capsid proteins and viral particles are found. Viral DNA is integrated in cancer cells, which contain no replicating virus. Once viral genome replication is completed, the expression of two virally encoded structural proteins, expressed in the upper layers of infected epithelia may occur. L1 the major capsid protein is expressed after L2 in a sub set of cells that express E4 (fig 2), this allows the assembly of infectious particles in the upper layers of the epithelium (Florin et al.,2002). A successful infection requires the virus to escape from the infected skin cell and survive extracellularly prior to re-infection. HPVs are non-lytic and are as such not released until the infected cells reach the epithelial surface. The intracellular retention of HPV antigen until the cell reaches the uppermost epithelial layers may contribute the compromised immune detection, especially as the virus has molecular mechanisms that limit the presentation of viral epitopes to the immune system in the lower epithelial layers (Ashrafi et al 2002). What are these mechanisms Figure 2 Papillomavirus type 16 Life Cycle and gene expression location within epithelium Taken from, The papillomavirus life cycle by John Doorbar published in the journal of clinical virology 32S (2005) S7-S15 Figure 2 diagrammatic representation of the skin with HPV type 16 gene expression incorporated, colour of arrows are representative of genes expressed within epithelial cells. The frequent detection of high risk HPV DNA in cervical lesions in the absence of any obvious disease, may be explained by the presence of the virus in a latent state, with only very few cells able to support the productive virus life cycle during epithelial cell differentiation. Following immune regression, HPV DNA is thought to remain in the basal epithelial cells waiting to be reactivated once levels of immune surveillance decline there are conflicting opinions (Zhang et al.1999). If regression is not achieved lesions may persist and in some instances progress to cancer. The number of lesion that progress to cancer is very low when compared to the prevalence of high risk HPV infection in the general public. The Progression of productive lesion to high grade lesions may result from the deregulation ( what happen to allow thes proteins to be deregulated intergrattion loss of E2 adn p53 association, be specific add biochemistry here please. in the expression of transforming proteins E6 and E7. The inability of a cell to support the whole virus life cycle is often associated with the development of cancerous lesions. The transformation zone (Fig 3) is particularly susceptible to cervical cancer; it appears that high risk types of HPV such as type 16 cannot complete their life cycle at this site Progression from CIN3 to cancer usually occurs in lesions that contain integrated copies of the viral genome in which E7 expression is elevated. Suggesting that retention of E6 and E7genes and the loss of E2 and E4 genes (that exert negative effect on cell growth) usually accompanies the development of invasive cancer. (reference) Remember for CIN refer to in that section or here but Cin must be corrulated with what causes the cancer and with whats happening with the virus that causes the change in CIN or the causes in CIN to occur. Cervical cancerisa considerable contributor to morbidity and mortality. Being the second most common cancer worldwide and the twelfth most common cancer in women in the UK. Cervical cancer in 2002 was the cause of 274,000 deaths worldwide (the most current data available)REF THIS FIGURE and continues to causes more than 1000 deaths in the UK each year. There are two main types of cervical cancer squamous cell cancer (the most common) and adenocarcinoma, although they are often mixed. They are named after the types of cell that become cancerous through neoplasia. Squamous cells are flat cells covering the cervix; adenomatous cells are found in the passageway from the cervix to the womb. Other rarer cancers of the cervix include small cell cancer. Deaths from cervical cancer in the UK have fallen over the last 20 years mainly because of the NHS cervical screening programme that reduced the mortality rates by 62% between 1987-2006. Screening may detect changes in the cells of the cervix at a pre-cancerous stage. Fig 3 TITTLE Showing location of transformation zone. Cell samples are examined for abnormalities, these abnormality are described in a standard format covering cytology and/or histology. What are these standard format CIN 1 CIN2 CIN3 LISL LGSIL HSIL HGSIL USE FIG 4 and explain whats happening with the proteins expressed and genome intergration where CIN number progression is concerned please. MUST DO From Lowy Schiller, J Clin Invest, 116:1167-73, 2006 Low grade squamous intraepithelial lesion (LSIL or LGSIL) indicates possiblecone biopsy, or laser ablation. High grade squamous intraepithelial lesion (HSIL or HGSIL) indicates moderate or severeCIN 2 or CIN3 (fig 3). While cervical screening has reduced the mortality significantly in the developed world cervical cancer is still a significant burden worldwide. Fig 4 Taken from, The popillomavirus life cycle by John Doorbar published in the journal of clinical virology 32S (2005) S7-S15 Fig. 5. CIN 1 resembles productive infections caused by other HPV types and as such is the most benign form of cervical intraepithelial neoplasia , it is confined to the basal 1/3 of the epithelium, CIN 2 Moderate dysplasia confined to the basal 2/3 of the epithelium,CIN3 Sever dysplasia that spans more than 2/3 of the epithelium, and may involve the full thickness. INCIDENCE An estimated 493,000 new cases and 274,000 deaths in 2002 were caused by cervical cancer. The vast majority, some 83% of these cases, occur in developing countries, where cervical cancer amounts to 15% of female cancers with a risk before age 65 of 1.5%. In developed countries cervical cancer accounts for only 3.6%, with a risk of 0.8% before age 65. REF The highest incidence rates are observed in Sub-Saharan Africa, Melanesia, Latin America and the Caribbean, South-Central Asia, and South East Asia (fig 6) Fig 6 Worldwide Burden of HPV related Cervical Cancer Figures from 2002. Parkin MD et al 2006 The burden of HPV-related cervical cancers The vast majority of cervical cancers are squamous cell carcinoma adenocarcinomas being less common (fig 6). Generally the proportion of adenocarcinoma cases is higher in areas with low incidence of cervical cancer, accounting for up to 25% of cases in western countries (fig 6). This higher incidence of adenocarcinoma may be partially explained by cytological screening, which historically, had little effect in reducing the risk of adenocarcinoma of the cervix, because these cancers, and their precursors, occur within the cervical canal, and were not readily sampled by scraping of the epithelium of the ectocervix. Fig 5 Fig 5 showing the higher % of adenocarcinoma in counties that have screening programmes such as the UK and Denmark What is this showing? Make it clear.do you really need it. MORTALITY RATES Mortality rates are substantially lower than incidence rates. Worldwide 55% (could you double chek that this is the case please misses) of all those that develop the disease die, the figures vary significantly from the developed to the developing world. Low risk regions of the west such as Europe have a death rate of 37% while in developing countries where many cases present at relatively advanced stages, death rates are significantly higher increasing to 70%. Cervical screening programmes in the developed world identify pre-cancerous lesions at a stage where they can be easily treated accounting for the difference in mortality rates. TITTLE IF and figure number staying and refer to in text As cervical cancer affects a relatively high number of young women, it is a significant cause of years of life lost (YLL) in the developing world. Yang et al 2004 found that cervical cancer was responsible for the 2.7 million (age weighted) years of lives lost world wide in 2000, and that it is the single biggest cause of years of life lost from cancer in the developing world. In Latin America, Eastern Europe and the Caribbean, cervical cancer makes a greater contribution to YLL than disease such as Tuberculosis or AIDS. HPV is also associated with many other forms of cancer that could possibly be prevented with use of HPV vaccines; cancers of the penis, anus, vulva, vagina, oropharynx and some rare cancers of the head and neck are included. However cancer of the cervix is by far the most significant, in terms of incidence and mortality (table 1). Cancer of the vulva and vagina have a significantly lower incidence rate compared to cervical cancer, however since 80% of the incidence are caused by HPV types 16 or 18 women vaccinated against these types would also be protected against these forms of cancer. Incidence of squamous cell carcinoma of the anus are twice as common in females as males with HPV types 16 and 18 accounting for 83% of all cases. There is a particularly high incidence of anal cancer among homosexual males, shown by the high incidence rate in populations such as Sanfransisco, where gay incidence are higher than average (fig 7). Globally cancer of the penis is relatively rare accounting for 0.5% of cancers in men (table 1). HPV DNA is detectable in 40-50% of all penile cancers and serological studies have confirmed the role of HPV 16 and 18 (IARC 2005). Cancers of the mouth and oropharynx caused by HPV are very low at 0.06% of all cancers with 0.05% being caused by HPV types 16/18. Due to the small size of most studies and the absence of comparable measurements of prevalence of infection in normal subjects conducted for cancers of the vulva, vagina, penis and anus true prevalence is difficult to quantify. The figures shown in table 1, imply that we are dealing with a virus that discriminates primarily through disease aginst women, in particular young women. Gay men, however are also clearly an at risk group. Currently only young women are vaccinated aginst HPV types 16 and 18, however the JCVI (joint committee on vaccination and immunisation) have noted that the vaccines has not been conclusively trialled on men, and that there is insufficient evidence that the vaccine available would protect against anal, penile or head and neck cancer. However when more data becomes available they will consider vaccinating, high risk groups such as men who have sex with men. Add what this implies for prophylactic use of vaccine with other cancers cause by HPV And what you think about the ue of vaccine on highrisk men and its effectivity against other cancers caused by HPV types 16 and 18. Fig 7 TITTLE add Figure 6 showing that cancer of the anus are more prevalent in women than men with the major noted exception being San Francisco, where the increased incidence can be explained by a large number of homosexual men. HPV INFECTION-ATTRIBUTABLE CANCER IN 2002: BY SEX AND HPV TYPE Table 1 MALES SITE ATTRIBUTABEL TO HPV % OF WHICH HPV TYPES 16 AND/OR 18 % TOTAL CANCERS ATTRIBUTABLE TO HPV ATTRIBUTABLE TO HPV THYPES 16/18 CERVIX 100 70 0 0 0 PENIS 40 63 26,300 10,500 6600 VULVA/VAGINA 40 80 0 0 0 ANUS 90 92 14,500 13,000 12,000 MOUTH 3 95 175,900 5200 5000 OROPHARYNX 12 89 42,500 5100 4500 ALLL SITES 5,801,800 33,900 28,100 Table 2 FEMALES SITE ATTRIBUTABEL TO HPV % OF WHICH HPV TYPES 16 AND/OR 18 % TOTAL CANCERS ATTRIBUTABLE TO HPV ATTRIBUTABLE TO HPV THYPES 16/18 CERVIX 100 70 492,800 492,800 344,900 PENIS 40 63 0 0 0 VULVA/VAGINA 40 80 40,000 16,000 12,800 ANUS 90 92 15,900 14,300 13,100 MOUTH 3 95 98,400 2,900 2,800 OROPHARYNX 12 89 9,600 1,100 1,000 ALLL SITES 5,060,700 527,200 374,700 Table 3 BOTH SEXES TOTAL CANCERS ATTRIBUTABLE TO HPV % OF ALL CANCERS ATTRIBUTABLE TO HPV TYPES 16/18 % OF ALL CANCERS 492,800 492,800 4.54 344,900 3.18 26,300 10,500 0.10 6600 0.06 40,000 16,000 0.15 12,800 0.12 30,400 27,300 0.25 25,100 0.23 274,300 8,200 0.08 7,800 0.07 52,100 6,200 0.06 5,500 0.05 10,862,500 561,100 5.17 402,900 3.71 VACCINATION An effective vaccine should stimulate a suitable range of immune responses, mimic or improve on the protection gained from a wild type infection with little side effects. Critically the vaccine should be inexpensive, easily administered, transported and stored to further reduce cost and maximise convenience, this is especially relevant in the case of HPV vaccine as those that are not protected by the screening programmes of the developed world would benefit the most, ease of administration and storage is paramount in the developing world as stability and healthcare is more sporadic, and people are often more remote. There are many different kinds of vaccines available, and different vaccines have a variety qualities and limitations. Live attenuated vaccines contain a version of the pathogenic microbe that is avirulent, they often elicit an excellent cellular and antibody response with good longevity that can be lifelong with few doses. However there is always the possibility that the vaccine may revert to its virulent form, causing disease. For this reason a live attenuated vaccine is not appropriate for use against oncogenic HPV types. Recombinant vaccines can include one or more proteins that may illicit an immune response. A process has been developed to allow the removal of the genome from an attenuated or avirulent viral vector allowing the insertion of selected genetic material or proteins from another virus. The carrier viruses then ferry that viral DNA into host cells where the genes are expressed. Recombinant vaccines closely mimic a natural infection and therefore illicit a strong immune system. Inactivated vaccines are produced by killing the disease causing microbe by chemical (formaldehyde eg just double check), heat or radioactive means. These vaccines are more stable than live vaccines, and as there is no risk of reversion to virulence. They are also safer than live vaccines. Most inactivated vaccines stimulate a weaker immune response than live vaccines and several doses or boosters may be required to maintain immunity. DNA vaccines dispense with both the whole organism and its parts. They only include the essential part of the microbes genetic material. In particular, DNA vaccines use the genes that code for immunogens. Researchers have found that when the genes for a microbes antigens are introduced into the body, some cells will take up that DNA. The DNA then instructs those cells to make the antigen molecules. The cells secrete the antigens and display them on their surfaces. In other words, the bodys own cells become vaccine-making factories, creating the antigens necessary to stimulate the immune system. A DNA vaccine against a microbe would evoke a strong antibody response to the free antigen secreted by cells, and also stimulate a strong cellular response against the microbial antigens displayed on cell surfaces. The DNA vaccine is unable to cause disease because it does not contain the microbe, only copies of a few of its genes. In addition, DNA vaccines are relatively easy and inexpensive to design and produce. It is likely that several doses or boosters would be required to maintain immunity. DNA vaccine are still in development and currently no one are licensed for use although they show great promisedouble check please. A subunit vaccine includes only the antigens that best stimulate the immune system. In some cases the vaccine uses epitopes. Subunit vaccines do not contain whole microbes or genetic information, reducing the chances of an adverse response significantly. Sub unit vaccines may include several antigens. In the case of Cervarix two different subunits are included, and in the case of Gardasil four different subunits are included. Identifying which antigen best stimulates the immune system can be problematic, once achieved subunit vaccine can be, made in one of 2 ways: 1)The microbe can be grown in the lab to high titres; chemicals (what chemicals)are used to break the microbe apart allowing the gathering of the relevant antigen. 2)Antigen molecules can be manufactured form the microbe using recombinant DNA technology. Vaccines produced in this way are called recombinant subunit vaccines Both Cervarix and Gardasil are recombinant subunit vaccines. WHAT are VLPs discuss these please And the process of making Cervarix and Gardasil Biochemical detail to include explanation of bacalovirus system and wehat genes they insert and how they do it. Full explanation please misses x x VACCINE USE Insert table of available vaccines There are several examples of diseases that have been controlled through successful vaccination programs (table 2) , the most successful and the only disease to have been eradicated is smallpox. Table 2 TITTLE Virus Administered Attenuated Inactivated Recombinant/Sub-unit Hepatitis A im X Hepatitis B im/sc X Influenza im X Japanese Bencephalitis sc X Measles, Mumps, Rubella (MMR) im X Poliovirus o/im X X Rabies im X (X) Smallpox sc X Tick-borne encephalitis im X Varicella-Zoster im X Yellow fever sc X Papilloma virus (16,18) im X Rotavirus oral X Refferncve source is DIDcks lectures can I really do this The vaccine for smallpox is a live virus preparation of vaccinia virus. The antibodies produced by/against vaccinia are cross reactive for smallpox. Vaccinia virus infection is very mild and is typically asymptomatic in healthy individuals check ther are someside effects. Live vaccinia virus vaccine can not cause small pox infections as it does not contain small pox DNA, so the risk that comes with a live attenuated vaccine does not apply here as the vaccine cannot revert to virulence. Estimated vaccine cost per vaccination in developing countries was 10 cents per vaccination, this very low cost allowed worldwide access. Freeze dried vaccine was mass produced in many countries reducing the risk of vaccine shortages, and the potency and stability of the vaccine was essential in the success of the programme. Novel administration techniques helped drive down the cost and expertise required; development of a new type of needle that could be reused after boiling contributed significantly. Success of the small pox eradication programme was also related to political commitment and leadership in the form of the World Health Organisation (WHO) and the Centres for Disease Control (CDC). Organisation of people on the ground by the WHO maintained motivation and focus, with small numbers of highly committed knowledgeable people, able to motivate large numbers of staff successfully, even in unstable areas and the poorest countries. This would have been more of a challenge without the backing received from many governments. Fig 8 TITTLE PLEASE When eliminated from more developed countries, public awareness was a key factor, with posters (fig 8) and leaflets used to educate the public about the dangers of small pox and encourage them to take up the vaccine. A combination of good science, outstanding organisation, focused monitoring, international commitment through governments, the WHO and CDC, coupled with high public awareness and low cost, easy administration of the vaccine was critical in the success of the smallpox eradication programme. There are elements directly linked to the smallpox virus that also helped in the eradication. Could say this bit in red more scientificallySmallpox has no zoonotic reservoir and as such only needed to be eradicated from humans to completely eradicate the disease. There is also only one strain of the virus that mutates very slowly, giving us the opportunity to succeed with the eradication before significant mutagenesis could occur. POLIO The introduction of a polio vaccine reduced the worldwide incidence of polio from an estimated 350,000 cases in 1988 to 1,652 cases in 2007. There are two vaccines used against polio, an oral live attenuated vaccine and an inactivated vaccine administer intramuscularly. The oral vaccine is easy and cheap to administered, an oral polio vaccine (OPV) is also advantageous in this case, as the virus replicates primarily in the gut, mimicking a true infection successfully. The attenuated strain of the vaccine may also be transmitted from person to person within the community providing wider protection than just those vaccinated. In regions without wildtype poliovirus, inactivated polio vaccine is the vaccine of choice. In regions with higher incidence of polio, and thus a different relative risk between efficacy and reversion of the vaccine to a virulent form, live vaccine is still used. The live virus also has stringent requirements for transport and storage which are a problem in some hot or remote areas. As with other live-virus vaccines, immunity initiated by OPV is likely to be lifelong. Is POLIO vaccine expensive? Poliovirus has no zoonotic reservoir and survival of the virus in the environment for an extended period of time is remote. Therefore similarly to smallpox, interruption of person-to person transmission of the virus by vaccination is the critical step in global polio eradication. These two vaccines and the implementation of their programmes haveeradicated poliofrom most previously endemic countries of the world. Public awareness was raised by poster, leaflets, radio, television and personal appearance of the character Well bee (fig 9) at public events in the United States. Fig 9 Public awareness poster for Polio Vaccination https://en.wikipedia.org/wiki/File:Polio_vaccine_poster.jpg Fig 9 poster of the CDC Well bee used in the US in the 1960s to raise public awareness of the polio vaccine The WHO in conjunction with UNICEF are hoping to eradicate polio as they did with smallpox, their campaign is ongoing. Only a handful of endemic countries remain; Afghanistan, India, Nigeria and Pakistan. The proposed deadline for eradication has been revised on a number of occasions due to financial and logistical issues surrounding the task. Measles Mumps Rubella (MMR) The MMR vaccination is given as part of the government immunisation programme in the UK. The MMR vaccine is a live attenuated vaccine that protects against Measles Mumps and Rubella. The fact that the vaccine is a combination vaccine means reduced administration costs. Even though the vaccine is given in the UK as a matter of course to children, when concerns surrounding its safety were raised and claims of connections between the vaccine and autism were made, a significant impact was seen on the uptake rate of the vaccine. In turn this meant increased incidence disease especially where measles is concerned. MMR is a good example of how a vaccination programme can be hit hard due to the public perception of risk and safety, even when the cost of vaccine and administration is low, government support and strategy of administration is well established, and efficacy of vaccine is high. There are posters and leaflets available for information on the safety and efficacy of the MMR vaccine. However it may take a significant amount of time to restore public faith in the MMR vaccine. Unfortunately the perceived safety of all vaccines can be adversely affected by media coverage, whether they are based on founded or unfounded data. THE VACCINES Insert introductory paragraph about why we need teh vaccine all you have said so far Is teh evidence for this. Must also describe The way in which they produce the vaccine background to development must also be included. Plenty of data on both Cervarix and Gardasil on your desk topo including info about how its made and the clinical trials and production of the vaccine C and P According to WHO, there were 510000 cases of cervical cancer in the world resulting in 288000 deaths each year. India has a higher burden with 130000 new cases and 75000 deaths each year due to cervical cancer. India has 25% of the global cervical cervical cancer burden by number of patients and deaths. Recent CDC data indicates that over 20 million Americans are already infected with human papilloma virus and 6.2 million new cases are detected every year. Each year 11000 cases of cervical cancer resulting in 4000 deaths in the US. Over 70 % of cervical cancer is caused by 2 strains of HPV 16 and 18 and 90% of anogenital warts are caused by 2 strains of HPV, 6 and 11, all four of these strains can be prevented by a quadrivalent vaccine Gardasil. About 1% of sexually active men have genital warts and over 10,000 women develop other types of genitalcancer due toHPV infectionseach year. Genital contact favors HPV transmission and spreads infection. In most of the cases (70-90%)our immun e system can overcome HPV infection and eliminate infected cells. Herald zur Hausen in Heidelberg during the 1977-1980 period, first isolated the HPV type 6 in human genital warts and later detected the presence of HPV 16 in 50% of cervical cancer cells and HPV 18 in 17-20% of cancer cells. The advent of PCR resulted in rapid detection of the HPV types in cervical cancer and so far over 106 types of viruses have been described. A pharmaceutical company turned down zur Hausen request to develop a vaccine in 1984. It was only in 1991 that the idea of HP virus as a leading cause of cervical vaccine was accepted and industry started development of HPV vaccine. The Nobel Laureate in his recent lectures has mentioned 500000 deaths per year from cervical cancer and 21% of global cancer burden due to chronic infections. https://knol.google.com/k/cervarix-glaxo-smith-kline-vaccine-for-cervical-cancer# Cervarix produced by Glaxo Smith Kline (GSK) and Gardasil produced by Merck are the two currently approved vaccines. Both are recombinant subunit vaccines made from the major capsid protein L1. Cervarix is a bivalent vaccine that targets HPV 16 and HPV 18 collectively responsible for 70% of cervical cancers. Gardasil is a Quadrivalent vaccine that targets HPV 16 and HPV 18, plus HPV type 6 and 11 responsible for more than 80% of genital warts. Both vaccines have been shown to be effective in preventing persistent infection with the targeted HPV types and in preventing cervical intraepithelial lesions. Virus like particles that form from the recombinant L1 protein mimic the native virus structure, but contain none of the viral DNA, meaning they cant infect cells or replicate within them. NOT enough information here refer to above HPV vaccines are highly effective; in clinical trials both Cervarix and Gardasil were over 99% effective at preventing pre cancerous and cancerous lesions caused by types 16/18 in young women (Harper et al 2006). How do we know how effective they are, how were they measured clinical trial information is on your desktop use this please. Both vaccines prevent infection by generating neutralizing antibodies against L1, blocking incidence infection. The vaccines use different adjuvants; Cervarix uses a new type of adjuvant, which GSK believes enhances its effectiveness, while Gardasil uses a more conventional adjuvant. Mention different adjuvants and different imunnogenicity as a result in your fuller explanation of the vaccines and their composition how they are made and their efficacy please my lovely. Both vaccines are very effective at protecting from incident infection with types 16 and 18. Although research funded by Gsk showed in a head to head trial that included more than 1100 women aged 18-45 that women who receive Cervarix had higher levels of antibodies than those receiving Gardasil 1 month after the final dose. Type 16 showed that levels induced by Cervarix were twice as high as Gardasil and for type 18 were more than 6 times higher. GSK claim that the new type of adjuvant used in their vaccine is partially responsible for the enhanced immune response. Several studies conducted with Cervarix showed more than 90% efficacy against incident infection (Harper.D.M et al 2004), (Harper.D.M et al 2006),100% efficacy against persistent infection (Harper.D.M et al 2004 )(Harper.D.M et al 2006), and 90.4% to 100% efficacy against HPV types 16 and 18 related CIN (Harper.D.M et al 2006).The vaccine was shown to be highly immunogenic with more than 98% seropositivity after 4.5 years (Harper.D.M et al 2006) now extended by Gsk to 7.3 years of sustained protection in women aged 15-25. Cross protection against incident infection with high risk HPV types 45 and 31 (types 16/18/31/45 account for more than 90% of cervical cancer cases) has also been seen with Cervarix (Harper.D.M et al 2006). As longevity of protection is not yet fully elucidated the need for a booster injection and its frequency if need is yet to be established; phase four trials are ongoing. For Gardasil estimations are that the vaccine is between 70 and 100% effective, with the life time risk of cervical cancer reduced to 47% and 30% respectively, compared to 86% risk with the current screening programme alone (Doling TS 2008). The duration of efficacy of Gardasil is not yet known but studies show good efficacy for at least 5 years(Wang KL 2007). Similarly to Cervarix it has not yet been determined whether booster doses are required for Gardasil. Both vaccines were shown to be most effective when administered before sexual debut and subsequent initial infection. The history of HPV infection and cervical cancer development in younger populations is is well understood, this is not so for older women. Although the highest incident of infection is seen in adolescents and early adulthood followed by a gradual decline with age, there is still a significant risk of new infection in sexually active women of all ages. We know that the introduction of new sexual partner is an increased risk and this can happen at any age. When women developed antibodies against a natural infection, the level at peak are generally very low (Vicidi RP et al 2004). Data from phase three Gardasil trials, showed that of the women aged 24-45 only a very small percentage, 0.35% had serological or DNA evidence of all types covered by the vaccine. A study has shown that women seropositive had the same risk of subsequent infection as seronegative women after 5-7 years (Vicidi et al 2004). Another study found that the risk of acquiring a new HPV type does not decrease among those with prior infection by a related or unrelated type. Although higher levels of antibody titer were seen in the younger vaccinated women it appears that there is only a very small proportion of women, those who are seroposative for all types conferred by the vaccine that would not benefit by receiving a vaccination. Even those seroposative for all type protected against after five years would have little protection from a natural infection. The decision to only vaccinate young women seems to have been decided by the high cost of the vaccine. DEVLOOPMENT AND DISTRIBUTION section must be added Include polyvalent vaccine in the pipe line Therapeutic vaccines and combination vacines Growth vectors technology/plants ect to reduce cost This is not inthe correct location fit it in somewhere more appropriate. Both Cervarix and Gardasil (the two currently available vaccines) fail to meet some of the criteria seen to aid in the success of past and current vaccination programmes. Both are very expensive at a cost of more than ÂÂ £300 in total for all three doses when compared to the low cost of vaccines such as the MMR or the vaccine against polio. The high cost of the vaccine currently rules out its use in developing countries. The administration strategy for both is also more complicated with three doses required over 6 months. With all three doses required to achieve maximum efficacy, ensuring that all three are given is important and logistically complicate in developed countries, in developing countries especially those that have a high population migration due to public unrest this will be nearly impossible to achieve. As neither vaccine are live the longevity of immunity may also be in question in years to c ome, as of yet there is no answer to whether a booster vaccination will be required. Incudes portical for both vaccine administration MUST DO Both vaccines are very effective, but an effective vaccine is not enough on its own to prevent disease. Public awareness of the efficacy and safety of the vaccine has to be raised by education through health care professionals, schools, posters, and leaflets as seen with succesfull and ongoing vaccination progemmes for smallpox, polio and MMR. Say they are using Cervarix please The vaccination programme followed in the UK was devised and implemented following advice from the joint committee of vaccination and immunisation (JCVI). Vaccine groups were originally split into two separate cohorts: Routine and Catch up The routine cohort is 12-13 year old females (born between 1 September 1995 and 31st August 1996) The catch up cohort is 17-18 year old females (born between September 1st1990 and 31st August 1991). Vaccination uptake figuers for those aged 14-18 are yet to be released as the vaccination campaign is ongoing, and should be completed by the end of the academic year 2009/2010 and therefore this aged group is excluded from this investigation. An overlap for the catchup cohort exsits due to the moving forward of those aged 17-18 to be vaccinated in 2008-2009 to include greater numbers of young women. Vaccination for both routine and catch up cohorts was implemented for the academic year 2008-2009. A high uptake rate is important where vaccines are concerned with regard to achineving herd immunity. In this case as the vaccine is only being given to young girls herd immunity cannot be achived consequently a high uptake rate is even more important, as reservoir of high risk HPV types exists in men and older women. Vaccination uptake in both cohorts was monitored carefully. This monitoring will allow the Department of Health (DOH) to facilitate the effective management of HPV programmes at all levels. Most importantly it will allow in the future the ability to analyse the benefit of the vaccination programme against what may be falling cervical cancer rates. The vaccination was given as per protocol and the uptake figures achieved could improve, especially where those who did not complete the course are given another oppertuninty for vaccination in the academic year 2009-2010. Several factors have already been seen to affect the uptake rate of the vaccine. FACTORS AFFECTING UPTAKE RATE stop think about what your trying to show here before you re arrange and edit, how much detail do you need. What you need to cover Location Choice over-under 16 Canhge of dates ofr cathcup cohort The setting in which the vaccination was given had a significant effect on the uptake rate. (fig 8). Both cohorts were vaccinated in a number of different settings including the school environment, the local general practitioner (where letters were sent to invite for vaccination appendix 1) and in some STI clinics. This will be less of an issue once the catch up programme is complete as vaccination will mostly be given in the school environment where the highest uptake rates were achieved check and change figures number please Fig 8 http:[emailprotected]/* */[emailprotected]/* */[emailprotected]/* *//documents/digitalasset/dh_111676.pdf Fig 8 showing a high uptake rate in the school environment, graph shows that of the PCTs with higher uptake % the vast majority of the vaccines were given in the school environment. The third dose uptake rate seen is much lower (fig 9); perhaps due to the lesser convenience, or possibly due to the availability of less information to allow an informed decision to be made. Those over 16 do not require parental consent and as such may make their own decision; this too may have a significant bearing on the uptake rate. Fig 9 http:[emailprotected]/* */[emailprotected]/* */[emailprotected]/* *//documents/digitalasset/dh_111676.pdf Fig 9 Catch up cohort shows a much lower uptake rate with those in the higher % over 40% being given mainly in the school environment. The differnce in uptake rate was particullary noticable where the third dose of vaccine is concerned. Whys that then? A direct comparison between school based doses 1, 2 and 3 and GP based doses 1, 2 and 3 shows a greater coverage rate achieved by the school based programme when compared to the GP based programme. Lower uptake rate for doses 2 and 3 in the catch up cohort may be partially explained by a change in the dates for beginning the programme; dates were pushed forward to 2008/2009 form 2009/2010. PCTs were only notified in June 2008 that the programme had been pushed forward given them little time to prepare, this my partially explain the lower figures but not fully. Letters were sent (example letters in the appendix) to all girls registered within a PCTS that were eligible but could not receive the vaccine at school, as they had left or because the school was not offering it. Non compliant patients were sent second letters asking them to confirm or decline their interest (example letters in appendix). Second letters were also sent to all patients who had dose 1 but not dose 2 and 3 (appendix). Table 4 Annual UK HPV vaccine coverage for females aged 12-13 years by country, 2008/09 HPV vaccine uptake % Country Dose1 Doses 1 and 2 All three doses NI 89.6 85.9 83.9 Scotland 93.7 92.7 89.4 Wales 87.9 87.0 78.8 England 88.1 86.0 80.1 UK 88.6 86.6 80.9 Across the UK 80.9% of those 12-13 years eligible for the vaccine received all three doses (table 4), with the highest percentages reached in Scotland where a more school based strategy for administration affected their overall uptake rate favourably. When uptake rates are compared with other developed countries the UK with regard to teh routine cohort compares favourably (table 5) , however as teh figures for those aged 14-18 years are not complete it is unfair to make a full comparison with other countries that have include wider age group. Table 5 International HPV vaccine uptake Country Third dose uptake % Delivery method Start date Evaluation period UK 80.9 Schools-based delivery to 12-13- year-olds Sept 2008 Sept 08 to Aug 09 USA 17.9* Through general practice to 13-17-year-olds Jan 2008 Jan 08 to Dec 08 Belgium 44** Schools-based programme to 12-15-year-olds Nov 2007 Nov 07 to Nov 08 Australia 66.3*** Schools-based programme to 12-18-year-olds Apr 2007 Apr 07 to Mar 08 Belongs with factors affecting the vaccination uptake rate Ethnicity religion and English as a first language are associated with acceptability of the vaccine in the UK. Girls form Muslim, Hindu or /Sikh backgrounds are less likely to have the vaccine. Support for this comes from studies of ethnic minority attitudes to HPV testing; where some women felt it reflected non-traditional cultural or religious practices concerning sex and monogamy and form ethnic differences in the use of sexual health services, where a major barrier for south Asian and African minorities is the cultural taboo around discussion of sexual matters. Perceived susceptibility, benefits and barriers were also associated with acceptability. Perceived risk of HPV within the ethnic minority groups was low because of their religious beliefs about sexual abstinence until marriage (Marlow LAV 2009). Another study has shown that ethnic minority parents are more likely to believe that HPV vaccination will result in an increase in risky sexual behaviour, a belief that has been sh own to be a barrier to HPV. A reduction in risk perception was also correlated with less likely hood of vaccine uptake in lowest income families, lack of education around the high risk of HPV and cervical cancer was seen as the reason. (Ref) Also seen was a correlation in safety fears surrounding the vaccine, with those parents less convinced that the vaccine is safe not consenting to is administration. As the vaccine is newly approved and phase four trials are still ongoing questions surrounding long term safety cannot be fully answered. While long term safety remains an important issue adolescent HPV vaccines coverage may; similarly to the MMR vaccine struggle to reach full coverage. Over 16s were seen to have some similar beliefs surrounding the vaccine with lower uptake rate seen in ethnic minorities. This is a worrying trend as it is suspected that those that do not take the vaccine would also be part of the 20% of total invited that do not take up their cervical screening appointment, putting them at extreme risk (appendix). The vaccine in the UK is given to young girls aged 12-13, parental consent is therfore applicable. Thus looking at the limiting factors of uptake rate diffetnt for for this demographic than it does for the catch-up cohort where the majority are over 16 and do not require parental consent. In the long term this will not be a consideration as the administration of the vaccine to those over 16 is time limited. Vaccines in the public eye Natalie Morton In excess of a million single doses of Cervarix have been given in the UK, only one was thought to be associated with the death of a young girl, Natalie Morton. It was quickly established that the real cause of death was a large and previously undetected tumour in Natalies chest that could have killed her at any moment; not from the Cervarix vaccine, this confirmed by the DOH appendix 2). Natalies death on 28/10/09 was covered extensively in the media and the vaccine batch in question was withdrawn and tested by two independent bodies and GSK, no abnormalities were found. Given the extent that the uptake of the MMR vaccine was adversely affected based on unfounded evidence, it is likely that this event will have some effect on the uptake of this vaccine. Data is yet to be published on the vaccination rates for 2009-2010 but information from a nurse working in the Warwikshire PCT (appendix3?) shows that three schools in Coventry (Natalies local area) have withdrawn from the vaccination programme. Since the evidence has shown that the best uptake rates are achieved when vaccinations are given in the school environment; implications for lower uptake rates due to Natalies death, even though unrelated, are already evident. Information surrounding the safety of this vaccine must be made clear to all possible recipients and their parents to allow informed decision rather than rash decisions to be made. The percentage of women screened for cervical abnormalities within the last 5 years has been falling slightly over the last decade, mainly in lower age groups. Data for 2006-2007 show that this is the second year it has dropped below 80% since the early 1990 (appendix 4). This is a concern as there is strong evidence that the death rate is lower in women first screened at a young age. This is clearly evident in developing countries with no screening programme, where the YLL due to cervical cancer are much greater than those of developed countries that do have screening programmes. The effect of the media with regard to Jade Goody, who famously and publicly died of cervical cancer on the 22 March 2009 at the age of 27 was significant. The public nature of her death prompted an increase in the number of women wanting information about cervical cancer and those attending cervical screening. Having interviewed a nurse who works for Warwickshire PCT and discussed with her the impact of the Jade Goody death her estimates were that for the two months following Jades death the screening rate doubled. However she was concerned that after this two month period the rate reverted back to its previous standings. Cancer research also experienced a significant increase in activity on their website. On the day that Jades diagnosis went public the figure increased from the usual 2-3000 to 32,000. They also claim that since then (August 2008) the number of hits per day is sustained at double the level they were before the public diagnosis (Correct to Feb 2009). The increase in the number of women being screened and the increase in information sought; shows that the influence of the media can both raise public awareness and prompt the general public into action. Stories such as those of Jade have had a huge impact. The level of raised awareness surrounding both the dangers of cervical cancer and the benefits of the vaccine must be sustained for the vaccination programme to be truly successful. People need to be encouraged to discuss any fears they have with a health care professional before making the decision to have the vaccination. CONCLUSION HPV vaccines; can they prevent cervical cancer? Go through one at time then delete this bit * Vaccine efficacy * Vaccine Cost/affordability/practicality of administation * Production and Distribution * Government backing and financial commitment * Other support organisations such as the WHO, UNICEF, Gates Foundation, Rotary International * Social factors * Media effects/Public awareness * Safety, and perceived fears Vaccine efficacy/longevity. The efficacy in preventing incident infection in types 16 and 18 for both vaccines is shown to be very high. Cervarix does have some increased protection against HPV types 31 and 45. The concern here is that both vaccines only protect against 70% of HPVs causing cervical cancer, what of the remaining 30%? Is it possible that the remaining high risk HPV types will become more prevalent in the absence of HPV type 16 and 18? There is not enough current data to compare population prevalence of other high risk types of HPV with the prevelence of HPV types 16 and 18 to allow this question to be answered. As we know cervical cancer is uncommon in women under 25 and is highest in women over 40 and as the oldest of the vaccinated cohort are 18 it will be several years before any real figures can be analysed. Screening will need to continue along with HPV typing for all cases of cervical cancer to allow monitoring of the possible success of the vaccine, to monitor for cervical cancer caused by the high risk types that are not covered by the vaccine, and to protect those that did not take up the vaccine or were not of eligible age. Cost affordability/practicality Both vaccines are very expensive, limiting use to more developed countries. Novel growth vectors are being explored in an attempt to lower the cost making the vaccine more widely available. A multivalent vaccine that protects against all types of high risk HPV would also be advantageous. There is a polyvalent vaccine in development that protects against nine high risk HPVs. If the cost of the vaccine was lowered to be affordable for developing countries the current regime of 3 doses over 6 months would not be practical. In the UK where the population is stable and also has easy access to healthcare the uptake rate of the third dose is significantly lower than that of the first two doses; adding our relevant limiting factors to the public unrest, mass migration, and sporadic healthcare in some developing countries it is clear to see that the current programme would be almost unattainable under these circumstances. Development/distribution Multiple therapeutic vaccines are in early development that may be more appropriate for those already exposed to high risk HPV types. Combination vaccines that are both therapeutic and prophylactic are also in development. DISTRIBUTION Support, governments/WHO/CDC/UNICEF The governments of many developed countries have shown support for the vaccine through the introduction of national immunization programmes. With the vaccines safety under question after the unrelated death of Natalie Morton greater effort needs to be made to publicise the well established safety of the vaccine. Media effects Public Awareness Can be good or bad but as they are free to publish only selected information they naturally select what will sell their products rather than report the full facts. This is unfortunate but in our free society is an inevitability that we have to work around as Jade Goody did Public awareness leaflets, posters and education are all important factors in maintaining a high uptake rate. Minorities that are more reluctant to have the vaccine should be targeted specifically with information pertaining to the dangers of cervical cancer and the benefits of the vaccine. MEDIA Safety Safety of the vaccines must be shown along with the few side effects seen after administration, this is critical to achieve a high uptake rate as was seen with MMR and more than likely due to the tragic death of Natalie Morton, if is question is raised regarding safety the take up rate could be reduced dramatically. Al current data indicates that the current HPV vaccines should prevent some incidence of cervical cancer by preventing incident infection of HPV types 16 and 18, new more novel vaccination will need to be developed to prevent cervical cancers caused by all HPV types. The long term efficacy of the current vaccine will also need to be monitored to establish if a booster is required at a later date to maintain protection. The Vaccination of other high risk group should also be considered. MORE Older women MEN ERADICATION is this a possibilityNO As the vaccine is only given to girls there is not protection by herd immunity as in essence men will continue to be a reservoir for HPV types 16 and 18, for this reason the uptake rate in women need to be as high as possible, no vaccine no protection at all. Could the vaccine be used to protect against other kinds of cancer? Yes more than likely however with the incidence of other cancers caused by HPV types 16 and 18 is so small that the vaccination programme at the current vaccination cost would not be cost effective. If there becomes available a multi valent vaccine that protects against more HPV types a t a significantly lower cost they could be given to men. Then possibly eradication, if the virus has no zoontic reservoir. Could the vaccine be used to protect against other kinds of cancer? Yes more than likely however with the incidence of other cancers caused by HPV types 16 and 18 is so small that the vaccination programme at the current vaccination cost would not be cost effective. If there becomes available a multi valent vaccine that protects against more HPV types a t a significantly lower cost they could be given to men. Will we ever eradicate HPV unlikely, will we ever eradicate oncogenic HPV. Who knows!!!!!! As of yet there is little evidence due to the newness of the vaccine to show that the vaccines will prevent cervical cancer at all. There is ample evidence that the vaccine prevents incident infection and that antibody levels are consistent for up to 7 years, Is the elimination of oncogenic HPV realistic Not with the current vaccines and not at the current cost Im afraid. My opinion Women of all ages should be able to take an informed decision when considering an HPV vaccination, 1 | Page

Speech Writing Services For College Students

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Whispered Undergraduate Essay Exam Samples Secrets

<h1>Whispered Undergraduate Essay Exam Samples Secrets </h1> <p>It is certainly not a basic sort of exposition as your comprehension of the subject should be put together not simply with respect to the data you get from another person yet generally on your own understanding. After you have assembled thoughts regarding the matter, you should appropriately set your musings into words. Evaluate another point and do exactly the same 5-minute composing test till you find a theme you realize it is anything but difficult to compose on. Indeed, even the most notable models need setting. </p> <h2>The Undergraduate Essay Exam Samples Pitfall </h2> <p>Such an exposition is aimed at recounting to a tale about a particular occasion in a person's life. A venture is something to assist you with turning out to be from a photographic droop, doing the specific thing again and again. </p> <p>Essay composing can be somewhat a test. 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Get The Best Use Out Of Your Key Phrases With Topic For Compare And Contrast Essay

Get The Best Use Out Of Your Key Phrases With Topic For Compare And Contrast EssayWhen you write a thesis paper and get to the point where you want to add topics for compare and contrast, you can use a combination of points that relate to the thesis you are writing about. Using them can make your presentation more interesting and help you distinguish yourself from the competition.Beginning questions are one way to use these examples. However, it is important to remember that you will be analyzing the same things as your competitors. Therefore, they will be used to show your uniqueness in comparison to what your competition will say.Common key phrases can be used by summarizing a section of your research or presentation. You may be thinking of some big, novel ways to summarize your findings. Of course, your chosen topic for compare and contrast essay will most likely have more to do with your example than the whole piece of work.For example, if you chose a main topics for compare and contrast essay on 'How Will Technology Affect the Future of Work?' You may be able to summarize the section as 'The way that computers are used to increase efficiency, reduce costs, and make the workplace more user-friendly.' If you choose to use examples like this, you can use the summary as a jumping off point for how the rest of your research should be presented.Use the ideas presented to write out each of the specific subject areas you are dealing with. When you write out each of the terms, you can then look at them and see if they match up to the big key phrases. You will find that most of the words that make up your examples are terms that would be used in your topic for compare and contrast essay.After you are done looking at your key phrases, it is time to take a quick inventory of all ofthe ideas that you came up with. You can now quickly compare your ideas against your examples.For example, if you used a computer as an example, you might find that the word 'computer' makes a reference to a number of things that relate to computers. Therefore, if you use computer as your topic for compare and contrast essay, you can then look at other ways to explain your statement by looking at the particular key phrases that make up the term.Once you have a list of examples that relate to your topic for the exam, you can go through them to see if they match your examples from your research. This is an easy way to use your examples as a springboard for how you can present your ideas in class.

Research Papers Should Compare And Contrast

<h1>Research Papers Should Compare And Contrast</h1><p>Research papers ought to be written so that they join an assortment of techniques for learning. The techniques are normally either composed or spoken, of a wide scope of exercises that are identified with the subject at hand.</p><p></p><p>One of the strategies for this sort of composing is known as referencing from different subjects information. In an overview it was discovered that understudies read a few fold the amount of as they were offered the response to an inquiry. In the examination paper we can allude to any number of different wellsprings of data so as to make the subject simple to understand.</p><p></p><p>This is the principle technique utilized by numerous journalists to assist them with finding out about the various sorts of materials out there. Another technique is to utilize a blend of the two strategies. In certain cases you will find that utilizi ng the two techniques is necessary.</p><p></p><p>The second strategy is to consolidate sources to clarify what is implied. Understudies with great order of one specific subject may experience difficulty understanding the material when they need to think about another source. It is the activity of the essayist to ensure that understudies can apply what they have realized in their exploration papers.</p><p></p><p>In request to do this you should consider what is said in different sorts of research papers in your subject. You should then place this into a solitary structure. This may seem like an undeniable arrangement, yet it will just turn out to be clear as you create examine papers that incorporate these methods.</p><p></p><p>When you first beginning finding out about research papers, you will find that you have to follow a couple of straightforward advances. These means incorporate reference from books, papers , and online assets. You ought to likewise consider consolidating some new ideas.</p><p></p><p>Once you have begun assembling research papers that are composed with reference from different sources then you can start to include your own. You can utilize these to better your evaluations on the course work and this will give you the experience you have to compose papers of more noteworthy complexity.</p><p></p><p>Hopefully you have discovered the data above accommodating in creating research papers that join parts of research strategies. The exploration papers that are composed with a blend of research strategies will be the ones that will stand apart to peruse. In the event that you can consolidate techniques, it will make your examination papers all the more fascinating and more useful.</p>

Argumentative Essay Samples For Grade 8

<h1>Argumentative Essay Samples For Grade 8</h1><p>Argumentative article tests for grade 8. Because you have a heavenly evaluation point normal, doesn't imply that it is a programmed pass. Most understudies get a passing mark by having the option to compose successfully and influentially, utilizing factious paper tests for grade 8. Perusing on this subject is an amazing method to ace article composing aptitudes, without investing a great deal of energy rehearsing the abilities at home.</p><p></p><p>Many understudies think about convincing exposition models, yet might be uncertain what they are and how they can utilize them. Convincing articles are papers written in a manner that convinces the peruser to concur with the author's contention. The paper test for grade 8 is really a progression of various sections or exposition subjects with the creator making a point about every theme. The focuses are connected together to make a bigger contentio n or subject. At the point when the exposition is done, the peruser can shape their own conclusion about the topic and will have taken in something from the essay.</p><p></p><p>There are various contentious article tests for grade 8 that can assist understudies with putting forth a powerful defense for an issue, thought, or philosophical conviction. Understudies may need to investigate this point further, just as examine their thoughts with others, so they can figure out how to introduce their assessment to other people. A convincing paper is an incredible method to begin building exposition composing abilities for grade 8.</p><p></p><p>Grade 8 is a significant year in an understudy's life. Since grades depend on one's presentation, not simply on one's capacity to learn and compose, understudies that don't perform well during grade school may wind up avoided from getting into secondary school, or being placed in unique projects. The be st paper models for grade 8 will incorporate articles composed by understudies who had solid exhibitions, in light of the fact that the aftereffects of the expositions will show what understudies were able to do, and why they proceeded as they did.</p><p></p><p>The best pugnacious exposition tests for grade 8 will likewise incorporate article subjects that allow understudies to think outside about the container, just as expounding on what they have gained from past encounters. A few understudies might not be able to gain as a matter of fact, or may have been separated too soon throughout everyday life, and consequently don't see the advantage of gaining from their encounters. Rather, they simply acknowledge what is and trust in their own numbness. The paper tests for grade 8 ought to give instances of different understudies who have learned by understanding, and how they have taken what they have realized and applied it to their own lives.</p><p>& lt;/p><p>Grade 8 is likewise a year that most understudies wish they could change. Life is frequently unjustifiable, and there are numerous obstructions that understudies face. Individuals appear to cause the day to go on without them, and they become progressively despondent. In these circumstances, understudies don't understand that they should stop and investigate the difficult they are confronting, and they will require help to explain it. A persuading contention can be their answer.</p><p></p><p>Argumentative article tests for grade 8 are valuable when understudies are searching for thoughts to kick them off on something that they can begin with. They are prepared to begin composing, yet they need thoughts that can kick them off. When they begin composing, they may feel that they don't have anything to expound on, and that they are finished composition. With an exposition test for grade 8, they can expound on their encounters and utilize the pap er tests for grades 8 to expound on their sentiments, and present a more clear contention about what they have realized, and how they learned it.</p><p></p><p>Although it is essential to compose with innovation and thought, it is similarly critical to introduce thoughts and points of view that different understudies can gain from. Understudies need to perceive what they definitely know, and how they can apply it to support the world. Factious exposition tests for grade 8 can be found at numerous sites, including those that permit understudies to download them.</p>

Essay Topics - How to Find Essay Topics

<h1>Essay Topics - How to Find Essay Topics</h1><p>Essay subjects are a significant piece of any composed bit of composing. You might need to locate some pleasant article points to use in your next project.</p><p></p><p>The primary thought behind composing is to uncover the essayist's musings and emotions about the given theme. The article can along these lines, advantage incredibly from the utilization of a paper point. Along these lines, you will have the option to advance your thoughts and character in a powerful manner.</p><p></p><p>Since expositions can extend from a couple of pages to a few hundred pages, it is frequently hard to track down article points that will be of adequate enthusiasm to your potential peruser. There are various things that you can do to help yourself.</p><p></p><p>If you are keen on composing an article, you ought to consider your own exceptional composing style. On the off chance that you are keen on composing a piece on a similar subject, it is best that you compose a theme in an alternate style. Along these lines, you won't commit errors when the opportunity arrives to consolidate your contemplations and insights.</p><p></p><p>It is best that you select the perfect subject that you need to expound on. A few people will incline toward subjects on their own social foundation, while others would like to have an article about something identified with what they know as of now. Remember that you ought to pick a theme that you are intrigued in.</p><p></p><p>You likewise need to recall that you ought not expound on a particular subject in the event that it doesn't intrigue you. The motivation behind an article is to impart to others about your specific information or mastery. That is the reason you ought to maintain a strategic distance from the utilization of redundant themes that will just get exha usting for your potential readers.</p><p></p><p>In expansion, exposition points ought to be straightforward enough for you to get a handle on. As it were, on the off chance that it is unreasonably unpredictable for you, at that point it will be unreasonably confused for other people. All things considered, the way to composing a decent exposition is to furnish your perusers with data that they will have the option to identify with. In such manner, it is significant that you read on various types of themes so as to figure out which ones are appropriate for your writing.</p><p></p><p>When you have discovered various great and explicit points, you should start to conceptualize various subjects. Your attention ought to be on how you can fuse the ideas or data that you have learned into a full essay.</p>

Dubai College Entrance Exam - How to Prepare For It?

Dubai College Entrance Exam - How to Prepare For It?The Dubai College Entrance Exam is one of the most important college admissions test conducted in the world. It is the test to show that individual belongs to a specific group. This test also serves as an exam to judge the knowledge and abilities of the candidates. Most of the candidates take this test to find their suitable colleges.If you are planning to go for admission in Dubai, then prepare well for the exam papers. In this regard, you must make sure that you study the details of the exam thoroughly. You can check out the appropriate examination websites to get the complete information regarding the exam.Since there are more than seventy percent females in the Dubai, girls should do well in this exam. However, it is not mandatory for them to enroll themselves into a certain college. They can make use of the free DCCE books available in the market. Since, it is compulsory for them to buy the exam samples, they can save a lot of money in the process. It is not very hard to get some of these books.There are many books which are available in the market which are the English books. These are also called Pre-Checker books. These books are usually printed by a certain exam publishers. The contents of the book are nothing more than a pre-test for the DCCE. Therefore, one can use these books to prepare the required details for the test.One can get the relevant help on how to prepare the required detail through a free exam study website. These websites are having some amount of classes for the candidates in order to prepare them well for the exam. These sites also provide a complete list of the questions of the exam. The question papers can be checked out in the right manner. Therefore, you can prepare yourself better for the exam by getting the complete details from the online database.It is not necessary for the candidates to have the same or similar grades at the exams. Some of the exams may even require you to complete the research or the project. All the contents of the question papers may vary in each exam. One can check out the complete details of the study guide before taking the exam.It is not necessary for you to prepare for all the items for the exam. All you need to do is to learn the basics of the contents of the exam and be able to take the proper answers for the question papers. Most of the time, the questions in these exams are easy. So, you need to make use of the study guides to solve the easy questions.

The Quintessential Handbook to Ielts Band 6 Essay Samples

The Quintessential Handbook to Ielts Band 6 Essay Samples The Tried and True Method for Ielts Band 6 Essay Samples in Step by Step Detail If you wish to know specifically where you're going wrong, then you have to examine your work with a seasoned IELTS instructor. Finding an IELTS band 7 in writing is quite challenging for many students, and many do not understand what the examiner is searching for. You are able to take my online IELTS Writing Practice Test anywhere on the planet and find a score, corrections, and feedback in only two days. Improving your grammatical accuracy is most likely likely to be a slow and gradual procedure. The One Thing to Do for Ielts Band 6 Essay Samples Where you are able to discover more sample essays for example. Here you will find a set of band 9 essay samples. Actually, prior to making an order you are able to secure a price quote on your essay. Several websites claim to provide this calendar year's IELTS essay questions. In reality, obtaining an idea about the the latest IELTS Essays has a competitive advantage as it gives someone an idea about the kind of essays he can expect in his exam on the 1 hand, and boost his preparation on the opposite hand. Within this post, we've composed several recent IELTS Essay topics to satisfy candidates who need to get a peek at those topics. If you search the internet for IELTS essay questions from using this calendar year, you will get a lot of results. There haven't been any considerable changes to IELTS essay topics in the past several decades. The 30-Second Trick for Ielts Band 6 Essay Samples To deal with all areas of the undertaking, you must respond to everything that's asked in the question. There's a lesson here that explains the significance of identifying the task to make certain you fully answer all areas of the question. Not each of the ideas have been put to use in the program. In a summary, the concept of damaging public property for virtual ly any reason isn't in any respect acceptable and society must curb the menace. Most of the folks within this world eat meat, whereas they are easily able to live by eating vegetables. People in modern society have a tendency to devote quite a long time on watching Youtube video, playing games with the most recent mobile apps as opposed to enjoying physical exercise. Children in some portions of the world have less responsibility in comparison with children previously. A more reason for people preferring cars is that they are easily able to transport a number of individuals at the exact same time and is especially safe for kids. The principal reason people are unable to conserve money is, their shopping addiction. It is crucial to remember, however, that there is not any such thing as a suitable answerthere is simply a well-developed, well-presented, and well-structured one. For instance, when a country does not have sufficient electricians, the entire electricity grid of that country may be at the possibility of malfunction. In case the nation or government fails to present these 3 things then the situation of the nation would acquire miserable. Getting the Best Ielts Band 6 Essay Samples What's the reason behind the growth in overweight individuals in society. Your writing also needs to be quite easy to read and all elements of it are managed properly so as to guarantee Coherence and Cohesion. Other individuals think that it has to be managed by individuals. There are several other strategies to safeguard the environment but there no other approaches to safeguard the rights of individuals. The N umber One Question You Must Ask for Ielts Band 6 Essay Samples Take a look at the questions and become familiarized with topics you would get on the true exam. The IELTS examiner is just interested in your usage of language, not in the caliber of your ideas. Vocabulary for IELTS Vocabulary is most likely the most essential part of preparing successfully for IELTS. Following current topics utilized in 2017 is vital for success in IELTS. Furthermore, the paragraph is coherent and there's a wide selection of language. Hopefully it will likewise contain some great ideas (i.e. vocabulary). An intriguing mixture of complex grammar structures will also need to be produced. Examples of great collocation include prejudices a reasonable trial and tackle the difficulties. You will require a wide variety and mix of these for an IELTS band 7, and you're going to want to be capable of using them effectively with some flexibility instead of mechanically. For this sort of employees, it's undeniable that a bigger circle of network and abilities acquirement bring them occupational pleasures. Skype is the best instance of an electronic communication which will cut the boundary that has separated each nation and earn communication between two distinct countries from all over the world possible. A Real Estate company unlike any other centered on the mission of constructing a network of career-minded pros who strive to cultivate their company and their future.

Confessions The Role Of Friendship On St. Augustine s...

CONFESSIONS: THE ROLE OF FRIENDSHIP ON ST. AUGUSTINE’S SPIRITUAL JOURNEY Originally written during the fourth century, St. Augustine’s autobiographical book, Confessions, was among the most influential models for Christian writers over the course of a millennium. As it is arguably Augustine’s most important text, it continues to influence theological discussion even today. Through writing Confessions, Augustine proves himself to be a professional scrutinizer. He analyzes every aspect of his own existence in pertinence to his purpose on Earth and relationship with God. Amongst the numerous topics covered in Confessions, Augustine makes exceptional mention to the role that friendship plays in his spiritual journey. In St. Augustine’s Confessions, the role of friendship is seen as both a method of ascending to God while also a being a means of drawing him further away through sin on his journey to spiritual contentment. Augustine’s spiritual journey ta kes place on a serpentine track outfitted with tempting divergent paths and disincentives that are scattered throughout the duration of his expedition. As just one of the many different aspects of his life, friendship plays an essential role in his journey; consequently, it is also one of the many things that Augustine scrutinizes under his theological magnifying glass. For Augustine, friendship is among the most vital facets of human existence and poses as one of the many puzzle pieces in forming the picture of who a person is

Applications For Hypertension Management - Myassignmenthelp.Com

Question: Discuss About The Applications For Hypertension Management? Answer: Introduction Apple Inc is a multinational technology company headquartered in Cupertico, California. The company develops, sells and designs online services, computer software and computer electronics (Apple 2018). The hardware products of the company includes iPhone, Mac personal computer, iPadtablet, iPod, the portable media player, Apple TV digital media player, Apple Watch and Homepod, a smart speaker. About the Product Apple Watch Series 3 is a third generation model of Apple watch, released in the year 2017 on September 22. The watch has an inbuilt long-term evolution (LTE) cellular connectivity and offers data and voice communication along with music streaming facilities. The watch has an electronic SIM card that can share the same mobile number as iPhone of the user (Rawassizadeh, Priceand Petre2015). The hardware of the watch has a dual core Apple S3 processor along with a red digital crown. The software of the watch is watch OS 4 that supports an updated heart rate app, workout app, two-way data synchronization that helps in integrating with various cardio fitness equipment. Target Market and Demographic Profile Apple Watch Series 3 targets the millennial since they are more receptive to technological innovation (Heracleous2013). They areknown as echo boomers whose characteristics vary depending on the region, economic and social conditions. Millennial have increased familiarity with media, digital technologies and communication. Definition of Consumer Behavior Consumer behavior refers to the study of groups, individuals or organizations along with the activities that associates with disposal, use and purchase of services and goods(Mullenand Johnson2013). This also includes considering consumers mental, behavioral and emotional responses that follows or precedes the activities. Scope of the Report This stage happens before the purchase of the product where it is important to identify the needs of the customers(Solomon2014). This creates an excellent opportunity for the marketers toadvertise their goods in a manner that is able to meet their needs. This also helps the customers to believe that their needs could be resolved. Psychological Influence Apple Watch Series 3 recognizes the need of the customers by incorporating the psychological influence. Apple Watch Series 3 has improved feature and functionality (Taylor2015). The biggest change brought to the customers is its additional feature of cellular connectivity. Moreover, Apple Watch users no longer need to keep themselves tethered to the iPhone since this product allows the consumers to receive and make calls, remain connected, receive and send text and stream music. Apple Watch Series 3 also have barometric altimeter along with a faster dual core processor. The Apple Watch Series 3 offers newer styles and bands that help owners in to demonstrate theirindividuality in varied colors and types. Search for Information This stage is the search stage of the consumer decision-making process. People have now progressed from old-fashioned shopping approach to onlinesearch engines(Oliver2014). People also gather information through word of mouth and previous experiences. This is the stage when the customers also think about risk management by considering the advantages and disadvantages that helps in easier decision-making. The best way a marketer can market to this need is by establishing the brand as a market leader. Psychological Influence: Apple recognizes the needs of the customers at this stage by incorporating psychological influence.Apple Watch Series 3 are available in two versions. One comes with onboard cellular connectivity while the other is available with GPS facilities(Starner2014). The non 4G version provides value for money and ensures fitness capabilities. This series 3 watch is a direct replacement of the series 2 watch category. However, both the versions have a chipset inside and are a flag bearer of longevity and fitness. This watch has cycle tracking and water resistant facilities along with facilities for heart rate monitoring. This watch haslatest operating software, WatchOS 4, makes the watch expensive. This watch acts as additional benefits for the fitness freak as it has apps that primarily focuses on fitness. The watch is available at a price of AU$459. Evaluation of the Alternatives This is that stage when the customers seem to place their queries regarding the product. At this stage, they try to analyze the real need of the product as a part of their well-being(Gunterand Furnham2014). Once the customer is convinces themselves about satisfying their needs they look out for the best deals in town based on quality, price and other factors that they consider important. Dealing with this stage cannot be easier for marketers. They can however meet this stage by placing the details of their product on their websites. Psychological Influence: Apple Watch Series 3 is not only elegant and light but has a 1.65-inch square display that helps in displaying better data. The screen makes use of organic light-emitting diode(OLED) technology that makes the watch more attractive. The watch also had a bright, vivid and clear display that allows greater view. The screen also automatically switches off in order to preserve battery(Akana et al. 2015). This implies that the wrist needs to be flickered for seeing the display. However, the algorithms of Apple are designed in a manner that a little flick is powerful enough to light up the display. This watch had the facilities of music streaming. The new version of Apple watch also has inbuilt cellular connection that allows it to work independently with the phone. This allows the users to not only receive calls but also receive app notifications. Call quality of Apple Watch Series 3 is quite impressive in terms of voice quality and sensitivity. Therefore, this watch allows users to have c onservation while running. The integration of the watch with the iPhone is also useful while driving. Decision for Purchase This is the stage when the customer decides to make a purchase based on the knowledge gathered. At this stage, they are assured about the place from where they want to make a purchase. This stage helps the customers to access all facts and thereby come to a logical conclusion based on advertising/marketing campaign or emotional experiences/ connections(Schiffman et al. 2013). This is the stage when the marketer needs to provide a sense of security thereby reminding the customers on why they made the purchase. Here the marketers also need to remind the customers that the brand can essentially fulfill their needs. The markets can also reinforce purchase decisions through email reminders. Psychological Influence The marketers of Apple can also follow this approach in addition to focusing on the motivating the customers for making a purchase. The purchase of Apple Watch Series 3 would be the best decision on the part of the users, as it will allow them to receive or make calls without even using a handset(Taylor2015). The LTE enabled Apple Watch Series 3 is automatically able to reconnect when there is a loss of connection. The entire display has LTE antenna and Universal Mobile Telecommunications System (UTMS) that provides excellent coverage inside and in outdoor. The Apple watches uses the same telephone number as that of iPhone and so the users have their calls routed to the watch. This series of phone also have complete data connectivity so that music streaming can happen directly from the wrist. Therefore, the watch allows users to stream music from the wearable device. The Apple Watch Series 3 has a built in Barometric Altimeter that helps tracking the activities of the users. This series of Apple Watch has made problem outdated, as they are able to track activity, the number of flights climbed and enable tracking of outdoor workouts that included elevation gain. This high technology watch allows asking Siri questions and hears the respond using the built in speaker of the watch. This is quite helpful while the user wants to send a text message while driving. The Siri will enable confirm the message by reading it to the user and sending it. Moreover, Apple Watch Series 3 has improved processor along with a wireless chipset. The new wireless chip also known as W2 enhances the ability of the watch in connecting to the Bluetooth and Wifi internet without sacrificing the life of the battery. Post Purchase Decision This is the review stage for the customers as well as the company. After purchase when the customer finds that the product has exceeded or matched promises more than their expectation they tend to become their brand ambassadors that helps in influencing other customers(Cohen, Prayagand Moital2014). However if the expectations are not met then negative feedback from the consumers also pour in thereby ending the journey of other potential consumers. In such cases follow up emails and surveys to the customers can be of help. Apple also considers the necessary feedback from the customers in modifying their products. Psychological Influence: Negative feedback from the consumers is bound make any company depressed however; Apple belongs to a category of company that uses negative reviews from its consumers to make necessary changes to its products so that they become easily acceptable the next time round(Kumar et al. 2015). Apple never feeds trolls as they come from people with wrong perspectives and could sometimes be contentious and disrespectful. The company also takes a pause before reacting and jumping into immediate actions. Apple therefore tries to affirm relationships with its customers with newer modified versions of its products. For this, they tend to prepare, understand interest, affirm relationships, searching for creative solutions and evaluating the options that are reasonable and objective. Key Recommendations The key recommendations to the brand for influencing the customers for purchasing the product are as follows: In terms of Fashion: Although the Apple Watch Series 3 is a high tech device, the company can push the style to envelope further. The company can thus collaborate with inexpensive brands like Target for increased customizationand decrease its price. This will enable Apple to optimize its product and appeal more to the masses. In terms of Independence: The reliance of the Apple watch on its iPhone is one of its biggest flaws. There is a need for the people tocarry the phones for facilitating Bluetooth connectivity that helped in enabling the function ability of the watch. Thus, without the iPhone the use of the watch becomes limited. Therefore, the watch is a more of an accessory rather than an independent device. Incorporating features that make the watch an independent entity that can encourage target customers to make a purchase. Incorporating Health App: Incorporating health metric and innovation analysis inthe latest Apple Watch Series 3 would not only monitor all facets of the wellness growth but would definitively enhance its popularity among the masses. Conclusion: The report ends by putting forward recommendations that would increase the sales of the Apple Watch Series 3. There is also discussion on the five stages of consumer decision-making process and how the Apple meets focuses on each of the stage through psychological influence. The report also gives a brief overview of the company, its products and the target audience along with their demographic profile. References: Apple. (2018).Apple Watch Series 3. [online] Available at: https://www.apple.com/apple-watch-series-3/ [Accessed 18 Jan. 2018]. Cohen, S.A., Prayag, G. and Moital, M., 2014. Consumer behaviour in tourism: Concepts, influences and opportunities.Current Issues in Tourism,17(10), pp.872-909. Gunter, B. and Furnham, A., 2014.Consumer Profiles (RLE Consumer Behaviour): An Introduction to Psychographics(Vol. 5). Routledge. Heracleous, L., 2013. Quantum strategy at Apple Inc.Organizational Dynamics,42(2), pp.92-99. Kumar, N., Khunger, M., Gupta, A. and Garg, N., 2015. A content analysis of smartphonebased applications for hypertension management.Journal of the American Society of Hypertension,9(2), pp.130-136. Mullen, B. and Johnson, C., 2013.The psychology of consumer behavior. Psychology Press. Oliver, R.L., 2014.Satisfaction: A behavioral perspective on the consumer. Routledge. Rawassizadeh, R., Price, B.A. and Petre, M., 2015. Wearables: Has the age of smartwatches finally arrived?.Communications of the ACM,58(1), pp.45-47. Schiffman, L., O'Cass, A., Paladino, A. and Carlson, J., 2013.Consumer behaviour. Pearson Higher Education AU. Solomon, M.R., 2014.Consumer behavior: Buying, having, and being(Vol. 10). Upper Saddle River, NJ: Prentice Hall. Starner, T., 2014. How wearables worked their way into the mainstream.IEEE Pervasive Computing,13(4), pp.10-15. Taylor, A.G., 2015. Common Features. InGet Fit with Apple Watch(pp. 3-8). Apress.