Vaccine in Cancer Prevention

Current Research Paradigm

  • Developing & improving cancer therapies
  • Early detection
  • Little attention on cancer prevention or risk reduction

Certain types of cancer take years to develop and there is an opportunity to intervene early in the process. The best opportunity to slow, stop, or reverse cancer development is with cancer prevention

Cancer vaccines

  • belong to a class of substances known as biological response modifiers
  • work by stimulating or restoring the immune system’s ability to fight infections and disease. There are two broad types of cancer vaccines:

Treatment vaccines are a form of immunotherapy. Majority used for treatment not prevention.

Sipuleucel-T (Provenge) à Dendritic cell vaccine à FDA Approved 2010 à  treatment of asymptomatic Androgen-Independent Prostate Cancer (AIPC).

Some of the patient’s white blood cells are removed, modified to recognize prostate cancer cells, and then returned to the patient. This is the future of personalized anti-cancer therapy.

Other vaccine under clinical trial-

OncoVAX for colorectal Ca, BiovaxID for Non- Hodgkin’s Lymphoma

Human Papilloma Virus (HPV)

  • Sexually transmitted HPV infection – most important risk factor for cervical intraepithelial neoplasia and invasive cervical cancer.
  • Causes of cervical cancer- HPV is a necessary cause of cervical cancer, but it is not a sufficient cause. Other cofactors are necessary for progression from cervical HPV infection to cancer. Long-term use of hormonal contraceptives, high parity, early initiation of sexual activity, multiple sex partners, tobacco smoking and co-infection with HIV have been identified as established cofactors; co-infection with Chlamydia trachomatis and herpes simplex virus type-2, immunosuppression, low socioeconomic status, poor hygiene and diet low in antioxidants are other probable cofactors.
  • Estimates suggest that more than 80% of the sexually active women acquire genital HPV by 50 years of age.
  • Vast majority à resolve spontaneously and only a minority (<1%) of the HPV infections progress to cancer
  • HPV currently causes as many deaths each year as measles caused in the pre-vaccine era

Indian Scenario

  • Every 7 minutes, an Indian die of cervical cancer
  • At a rate of 113 age adjusted DALY per 100,000 populations, India accounts for 26.5% of global cervical cancer DALYs
  • Due to high number of cervical cancer cases in the population, it has highest total cost of secondary care as compared to all other cancers.
  • 2nd leading cause of female cancer in india and …accounting to nearly 1/3rd of the global cervical cancer deaths.

Goldie et al-  estimated in countries like India, if more than 70% of the target populations (adolescent girls) are vaccinated then mean reduction in the lifetime risk of cancer will be more than 50%.

Why vaccination is the best form of prevention ?

  • No clear evidence – barrier methods of contraception, most notably use of condoms, confer a protection against HPV infection.
  • Secondly, except for genital warts, the infection is asymptomatic.
  • Adherence to routine screening by the susceptible female population through periodic Pap smears even in developed countries has been unsatisfactory.         

HPV vaccine

  • Recombinant DNA technology – express the L1 major capsid protein of HPV in yeasts (Saccharomyces cerevisiae), which self-assemble to form empty shells resembling a virus, called virus-like particles (VLPs).
  • VLPs – have same outer L1 protein coat as HPV but contain no genetic material.
  • VLPs – induce a strong protective immune response
  • exposure à vaccinated person à antibodies against the L1 protein will coat the virus à prevent releasing of its genetic material.
  • These vaccines do not protect against the serotype with which infection has already occurred before vaccination.
  • Use of 9-Valent Human Papillomavirus (HPV) Vaccine: Updated HPV Vaccination
  • Recommendations of the Advisory Committee on Immunization Practices
  • HPV 9- Covers additional oncogenic types 31, 33, 45, 52, 58
  • These types cause about 15% of all cervical cancers
  • In total, vaccine covers types that cause ~81% of cervical cancer

Efficacy- Immunogenicity studies in females aged 9–15 years showed antibody titers non-inferior to those aged 16–26 years.

At 18 months post vaccination, anti-HPV titers in younger patients were two- to three-times higher than that in older patients

Persistence of Immune Response

  • Evaluationà immunogenicity data at the interval after the first vaccine dose with a median follow-up of 9 years.
    • Resultsà 100% (95% CI: 96.1;100) remained seropositive for HPV-16 and HPV-18 in the ELISA assay.
    • So far, the follow-up in the vaccine trials has been for a period up to 9.4 yr.
    • The total duration of protection is not yet known.
    • Data correlating antibody persistence with protection is also awaited.
    • At present data do not support the role of a booster dose.

Cross-protection

bivalent vaccine has demonstrated

  • 78 % cross-protection (range: 39–93%) against incident infection with HPV-45
  • 60 % cross-protection (range: 20–81%) against HPV-31

What does the vaccine not protect against?

  • As many as 30 per cent of cervical cancers will not be prevented by the vaccine
  • Thus, vaccination is not a substitute for cervical cancer screening
  • Also, the vaccine does not prevent about 10 per cent of genital warts nor will it prevent other STIs.

Do we need HPV vaccination in boys?

  • Oropharyngeal cancers are more common in men.
  • There is no screening test for oropharyngeal cancer.
  • HPV-related tongue and tonsil cancers have more than doubled in the past 20 years.
  • The question of male vaccination is still debated. Some countries have licensed the vaccine for use in boys as well. The case for male vaccination against HPV relies on the establishment of herd immunity, thus reducing the chances of an infected individual transmitting the virus to a susceptible person. However, this increases the cost of vaccination two-fold. Since the quadrivalent vaccine immunizes against HPV types that cause genital warts as well, it is more likely to be taken up by teenage boys.
  • HPV vaccine is not licensed for use among males in India.
  • Australia is the first country to approve the quadrivalent HPV vaccine in males (between 9 and 15 years old), and the vaccine was approved for administration to males between the ages of 9 and 26 years in other developed nations.

Effectiveness of HPV Vaccine School Campaigns

  • Australia’s HPV vaccination program is one of the most successful in the world,
  • Startedà 2007,
  • offers free HPV vaccination to girls who are 12 and 13 years old and catch-up programs for girls and women under 26.
  • Studies haves shown a striking decline in the rate of high-grade cervical abnormalities in teenage girls
  • Australia now has the lowest cervical cancer prevalence in the world.
  • Genital warts in women < 21 years old  decreased from 18.4% in 2004 to 1.1% in 2014

HCP’s Recommendation

  • Parents with a healthcare provider’s recommendation are much more likely to vaccinate

Indian Academy of Pediatrics Recommendation

  •  HPV vaccination be offered to all female patients aged between 9 and 26 years, who can afford it. 
  • Because protection is seen only when the vaccine is given before infection with HPV, the vaccine should be given prior to sexual debut.
  • Vaccines are not 100% protective against cervical cancer and not a replacement for periodic screening. 
  • Both vaccines available are equally efficacious and safe for protection against cervical cancer and precancerous lesions as of currently available data. The quadrivalent vaccine has, in addition, demonstrable efficacy against vaginal and vulvar cancers and protects against anogenital warts.

Issues in Indian  Scenario

  • The primary obstacle à financial.
  • high cost of the present vaccinesà affordability and accessibility of these vaccines is a major concern for a mass vaccination program.
  • Unsuccessful HPV Vaccine trial- led by ICMR and PATH.
  • India’s Parliamentary Standing Committee on Health and Family Welfare investigated the clinical trials of the HPV vaccine following the death of seven participants. This trial was jointly led by ICMR and PATH, a USA-based organisation, with funding from the Bill and Melinda Gates Foundation. The committee noted that the ICMR became a direct party in the study through its presence in the project’s advisory committee. Also, the manufacturers conducted this vaccine trial in the department of obstetrics and gynaecology of All India Institute of Medical Sciences (AIIMS) whose head of department was appointed as a member of the inquiry committee. This was a clear instance of COI as her findings could not be relied upon. This trial was stopped later.

Lacunae and future

  • More research àduration of protection

                                   à need for boosters

                                   à effect on prevalence and incidence of HPV types

                                   à efficacy in females older than 26 years                                                     

      à efficacy in males needs to be conducted.

  • epidemiological studies à long-term efficacy, logistics and economics of universal HPV vaccination in eligible females.
  • Some of the new generation of vaccines under study are – additional VLP types (HPV-31, -45, -33, -52, etc. in nonavalent formulation), heat stabilized VLPs, slow release formulations, oral vaccines and chimeric VLPs.

Hepatitis B Vaccine

  • HCC is one of the most common causes of cancer death worldwide.
  • more than 2 billion individuals worldwide present serological evidence of hepatitis B infection. Of these, 400 million are chronic carriers, and between 0.5 and 1.2 million die annually from cirrhosis and HCC
  • poor prognosis in most occasions and a high recurrence rate after therapy.
  • Therefore, prevention is more effective than therapy.

HCC – predisposing factors

  • viral hepatitis B- most important etiologic agent – causes 60–80% of the HCC globally.
    • most common cause of infection related cancer deaths
    • Mother-to-infant transmission is the major source of chronic HBV infection (approximately 40–50%) in Asia.
    • Persistent viral replication with elevated serum HBV DNA level (>10,000 copies/mL) is a strong risk predictor of HCC.
  • Viral hepatitis C
  • Alcohol
  • obesity,
  • iron overload,
  • and dietary carcinogens including aflatoxins and nitrosamines

HBV Vaccine

  • The world’s first universal HBV vaccination program was launched in Taiwan in July 1984.
  • It is the first example of cancer-preventive vaccine in human, which proves that prevention of the infection of an oncogenic infectious agent can prevent its related cancer.
  • Approximately 90–95% the incidence of chronic HBV infection in children has been reduced remarkably in areas where universal HBV vaccination in infancy has been successfully introduced.

HBV vaccine – Schedule

  • Paediatric dose vaccine: 10 mcg dose (in 0.5 ml suspension) upto 19 years of age.
  • Adult dose vaccine: 20 mcg dose (in 1.0 ml suspension) is recommended for adults aged 20 years and above.
  • Primary immunisation

The following immunisation schedules can be recommended.:

  • 6,10,14 weeks for infants
  • 0,1,6 months
  • 0,1,2 months (rapid schedule)
  • Booster dose – full primary immunizationà not recommended
  • Recommended à  Anti- HBs antibody titres fall below 10 IU/L for all people at risk
  • In clinical trials, 91 % – 100% of healthy infants, children, adolescents and adults given a 3 dose course of recombinant hepatitis-B vaccine developed a protective level of antibodies against hepatitis-B virus surface antigen (≥ 10 IU/l).

HBV vaccine survey – Taiwan

  • Serial epidemiologic surveys of HBV markers were conducted before and 5, 10, 15, and 20 years after the implementation of the  vaccination program in Taiwan
  • The HBsAg carrier rate decreased significantly from around 10% before the vaccination program to 0.6–0.7%
  • The total infection rate (anti-HBc seropositive rate) declined from 38% to 16% and further down to 4.6% in children 15–20 years after the program

HBV vaccine coverage -India -87%

In developing countries like India with limited resources, immunization with three doses of HBV vaccine in a 0-, 1-, and 6-month schedule without antenatal screening of the maternal HBV markers and administration of HBIG is an effective and economic way for HBV infection and hepatoma control.

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