Cervical cancer vaccine: Exploring new opportunities and challenges for developing countries

Cervical cancer is the second most common cancer in women worldwide, and the burden of the disease is disproportionately high in the developing world (>80%). With the advent of two new vaccines, “Gardasil” developed by Merck & Co. New Jersey, USA and “Cervarix” developed by GlaxoSmithKline (GSK) in Philadelphia, USA, the future holds newer promises for prevention and control of the disease. However, various regulatory and policy changes also may be required to be undertaken and the various new challenges need to be addressed.

Keywords: Cervarix, Gardasil, human papillomavirus vaccines, screening methods, vaccination strategy

Cervical cancer is a major global health problem, with more than 130,000 new cases being reported each year and an estimated 74,000 women die from it annually, as per World Health Organization (WHO). It still remains the most common cancer among women in developing countries where a large majority are identified at an advanced stage. ^[1] In India alone, 10,000 new cases occur annually and around 70% of them are at Stage III or higher at the time of detection. ^[2] This is a public health tragedy, since among all major human cancers, cervical cancer is potentially the most preventable. ^[3]

Human papillomavirus (HPV) infections are very common among sexually transmitted infections and the lifetime risk of acquired HPV infection is 70-80% in many developing countries. The high-risk types of HPV are types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68. The risk for any of these types is the same, and the risk related to the presence of multiple-HPV types is no different from that of a single-HPV type. ^[4] A meta-analysis done at the International Agency for Research on Cancer (IARC) included a total of 10,058 cervical cancer cases from 85 published studies. The most common HPV types identified were, in order of decreasing prevalence- HPV 16, 18, 45, 31, 33, 58, 52, 35, 59, 56, 6, 51, 68, 39, 82, 73, 66 and 70. ^[5]

Evidence exists that the immune response to cancer cells can play a major role in determining the outcome of disease. The fact that “HPV is a necessary cause for cervical cancer” had provided a clear opportunity to develop a therapeutic or prophylactic vaccine against the virus. Two new vaccines, one quadrivalent vaccine “Gardasil” (against HPV-6, -11, -16, and -18) developed by Merck and Co. (NJ, USA) and approved in June 2006 and one bivalent “Cervarix” (against HPV-16, and -18) developed by GlaxoSmithKline (GSK) (likely to be approved soon), will act as weapons against occurrence of cervical cancers. ^[6]

Interim data from a Phase III clinical trial with more than 18,000 women from around the world showed that GSK candidate HPV vaccine, Cervarix, was 90% effective in preventing significant cervical pre-cancers (CIN 2 or higher) related to HPV types 16 and 18, and also offered partial protection against three other “high risk” HPV type infections. ^[7]

A new study showed that Cervarix induced antibody levels against HPV 16/18, at least twofold higher in 10-14 year-old adolescent girls than in 15-25 year old women. It may have important implications as the elevated levels demonstrated will result in longer duration of protection. ^[8] The vaccine given in series of three 0.5 ml intramuscular injections at 0-1-6 months was well tolerated and no vaccine-related serious adverse events were reported in any of the groups. ^[7],[8] The above results were presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Washington DC, USA. ^[7] Widespread use of the vaccine alone has the potential to reduce cervical cancer deaths by 50% over several decades and some estimates anticipate an even higher prevention rate of 71% depending on immunization coverage. ^[9],[10]

Another HPV/cervical cancer vaccine, Merck’s Gardasil, was approved in the US in 2006 and has been registered in more than 70 countries by 2007. The vaccine is currently approved for the prevention of cervical cancers and pre-cancers, related to two “high risk” HPV types (HPV types 16 and 18). Gardasil is also licensed for the prevention of genital warts associated with “low risk” HPV types 6 and 11. ^[8] In clinical trials, Gardasil prevented virtually all persistent infections and diseases related to the four HPV types covered by the vaccine. ^[11] It is to be given in a series of three intramuscular injections at 0-2-6 months. ^[8]

The Indian Council of Medical Research (ICMR) collaborated with the US-based Merck and Co., Inc., to study the effect of cervical cancer vaccine, Gardasil (quadrivalent HPV types 6, 11, 16, 18, recombinant vaccine), on the Indian population. Their motive was to determine the role vaccination may play in reducing the burden of cervical cancer in India. ^[12]

HPV vaccine is currently indicated for girls aged 9-26 years. ^[13] In several countries, including the United States, Canada, Australia, Austria, Italy, Germany and France, HPV vaccination has now been universally recommended. Other countries, including the UK, are considering recommendations for its use. ^[14],[15] Till date, only few side effects have been documented. Eighty percent of the patients complain of pain at the injection site. Some experience local swelling, redness, itching, fever or nausea. ^[15]

Cervical cytology screening has reduced cervical cancer morbidity and mortality but shows important shortcomings in terms of sensitivity and specificity. Moreover, screening demands facilities for call back and proper referral, irrespective of the screening strategy, without which it is a futile exercise. ^[14]

Some authorities believe that a positive Paps smear is too late and the damage leading to cancer has already begun. ^[16] HPV genotyping have been carried out to screen the population “at risk” using polymerase chain reaction (PCR) which unfortunately is exorbitant for developing countries. Even condoms do not provide 100% protection. ^[17] In a cost-effectiveness study conducted in rural India, cytology was found to be more effective at detecting cases than visual inspection by acetic acid (VIA) but was also more expensive. Their findings indicate that HPV testing may not be a cost-effective screening strategy in India at current consumable prices. ^[18] So, vaccination of pre-teen/adolescent girls against cancer-causing HPV before onset of sexual activity can prove to be a crucial and cost-effective adjunct to the overall strategy for cervical cancer prevention.

Implementation of a vaccine administration program is an area of opportunity for new policies to include pharmacists in the administration of prophylactic HPV vaccines. As of now, pharmacists have been allowed to administer vaccinations in 46 states in the US and can potentially play a role in HPV vaccine administration. For this to happen, however, multiple legal and regulatory changes must occur. Various regulatory and policy changes also may be required to be undertaken.

Recommendations for the Use of HPV Vaccines in National Program

1. The primary target population should be young adolescent girls as vaccination is most efficacious in girls who have not become sexually active. So, the programs should determine the primary target age group based on data on the age of sexual initiation and/or the feasibility of reaching young adolescent girls through schools, health-care facilities, or through community-based methods. ^[19]
2. Studies show that the following combinations of co-administration are safe and do not appreciably impair the immune response to any antigen: the quadrivalent vaccine with a recombinant hepatitis B vaccine, the quadrivalent vaccine with a DPT and vaccine, and the bivalent vaccine with a DPT and inactivated poliomyelitis vaccine. ^[20]
3. Vaccine delivery strategies: school-based programs, pulsed delivery through child health days, vaccination days, periodic campaigns, routine provision through health facilities, or combination of strategies can be adopted. ^[19]
4. Use of vaccine delivery methods that are compatible with delivery infrastructure and cold-chain capacity, which are affordable, cost-effective and sustainable for Indian conditions and can achieve the highest coverage.
5. Periodic surveillance should be conducted to identify possible, rare, unexpected adverse events through existing passive reporting systems or new sentinel studies, and also to gather the experience of other countries using these method ^[9]
6. Education of parents, caregivers and community: Information, Education and Communication should stress that HPV vaccines are intended to prevent cancer; they are not therapeutic or curative; are most effective when given before onset of sexual activity; and will not prevent HIV or other sexually transmitted infections or pregnancy. Messages should also stress that vaccines should seek cervical cancer screening later in life.
7. For resource-poor settings, inclusion of vaccination in national programs will be possible only with substantial subsides.
8. More cost-effectiveness analysis and research of various possible vaccination strategies should be undertaken.
9. Intersectoral coordination between Reproductive and Child Health as well as cancer control program is required to analyze the appropriate strategies and build national consensus.

Where do we go from here

While scientists say that vaccination could slash infection rates, however, its cancer-preventing benefits will not be evident for decades, as it will take that long for vaccinated girls to reach an age when they might otherwise have developed cancer. Meanwhile, millions of women who are already infected must be screened and treated. If there is widespread resistance to vaccination, it will take even longer for its benefits to become clear. Of late, some conservative lobbies in developed countries expressed that “abstinence or increasing the age of marriage is still the best way to prevent HPV infections at an early age”. They are of the opinion that “giving the HPV vaccine to young women could be potentially harmful because they may see it as a licence to engage in premarital sex”. ^[20]

It may take several years before this approach becomes a reality. But whenever it happens, HPV has to be introduced in the framework of comprehensive cervical cancer control program.

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1755-6783.80540