GlaxoSmithKline (GSK) announced on July 17 that Cirex® (human papillomavirus vaccine [types 16 and 18]) received marketing approval from the China Food and Drug Administration (CFDA), making it the first HPV vaccine approved to prevent cervical cancer in China.
Together with cervical cancer screening, HPV vaccination will provide Chinese women with a better means of preventing cervical cancer. GSK has also expressed its support for the inclusion of Cirex® in the national immunization program. This cannot but be a blessing for Chinese women.
Which HPV vaccines are available worldwide
HPV vaccines are divided into therapeutic HPV vaccines, which are under development, and preventive HPV vaccines, which are already on the market.
The FDA has approved three HPV vaccines that can effectively prevent HPV infection: Merck’s GARDASIL® (GARDASIL) and GARDASIL®9 (GARDASIL, a nine-valent recombinant human papillomavirus vaccine) and GlaxoSmithKline’s Cervarix. GARDASIL® is a nine-valent vaccine covering HPV types 16, 18, 31, 33, 45, 52 and 58, and Cervarix is a bivalent vaccine covering HPV 16 and 18. Among them, GARDASIL®9 is a new vaccine approved in 2014.
In China, GlaxoSmithKline’s (GSK) Cervarix® is the first HPV vaccine to be marketed. There are currently five drug companies that have been approved by the CFDA to enter the clinical setting for HPV vaccines, and 11 drug companies have submitted clinical applications, mostly for bivalent, trivalent, quadrivalent and hexavalent vaccines.
When HPV infects tissues, some of the virus can be self-limited and cleared by the body, but if the virus persists and infects, it may eventually develop into cancer. It has been confirmed by numerous studies that persistent infection with high-risk HPV types is the underlying cause of cervical precancerous lesions and cervical cancer. And in the natural course of HPV infection, the highest rate of HPV infection is found in women around 20 years old.
The number of new cervical cancer cases in China each year accounts for about 12% of the world
According to the 2014 WHO World Cancer Report, in 2012, China was estimated to have approximately 62,000 new cases of cervical cancer, with an overall incidence rate of 9.4/100,000 people/year. Although the incidence rate is lower than the East Asian region and the world average, China accounts for 12% of the global number of new cases each year due to its large population base.
Cervical cancer is the second most prevalent cancer among women aged 15 to 44 years in China, with about 130,000 new cases each year. Each year, China accounts for more than 28% of cervical cancer cases worldwide. Globally, on average, one new case is detected every minute and one woman dies from cervical cancer every two minutes.
Nine cancers are closely linked to HPV infection
In 2008, German scientist Harald Chur-Hausen won the Nobel Prize in Physiology or Medicine for revealing that cervical cancer is linked to HPV. However, high-risk HPV types not only induce cervical cancer, but also other cancers. According to a recent molecular epidemiological survey in the United States, the presence of high-risk HPV type DNA can be detected in the following nine cancers, especially in cervical carcinoma in situ, anal cancer, and cervical cancer, where the distribution of HPV genes is up to 90% or more.
Principles of HPV vaccine action
1. HPVVLPs induce a strong humoral immune response, with antibody titers typically 10 to 100 times higher than natural infection.
2. immune responses that occur at younger ages produce higher antibody titers, and age-specific antibody titers are also higher in those immunized at younger ages (e.g. both are higher in those vaccinated at age 12 than in those vaccinated at age 15). The duration of efficacy of HPV vaccination in childhood remains unclear.
3. slightly higher antibody titers in males than in females
4. 2vHPV induces higher antibody titers against HPV16 and HPV18 than 4vHPV, and also induces higher antibody titers against off-target HPV genotypes. For both 2vHPV and 4vHPV, antibody titers after immunization enter a plateau after a peak period of 1 to 2 years and remain stable for 8 to 9 years for continued prevention of HPV infection. 2vHPV vaccine has slower long-term antibody titers than 4vHPV vaccine.
The antibody titer threshold for HPV prophylaxis remains unclear, and antibody titers may be associated with prophylaxis but should be within a certain range to be fully functional. the combination of HPV vaccine with other vaccines (e.g., hepatitis A, hepatitis B, meningitis, tetanus, diphtheria, and pertussis) does not affect the immune response to HPV and can be administered concurrently with other vaccines.
Who should be vaccinated
Population effectiveness decreases with increasing age. HPV-related cancers occur more frequently in females than in males, so adolescent females are better off with HPV vaccination than adult females or adolescent males. There are no studies to compare, but the order of vaccination is adolescent females, adolescent males, adult females, and adult males.
The CDC and the American College of Obstetricians and Gynecologists recommend vaccination for women aged 9 to 26 years, and HPV vaccination is also recommended for HIV-infected women aged 9 to 26 years. Girls are encouraged to get HPV vaccination before the age of exposure to HPV comes. Of course, the age limit is not absolute, but it depends on the presence of sexual life. The HPV vaccine works best for women with no history of sexual activity, and the chance of HPV infection increases with sexual activity, and the preventive effect of the vaccination decreases.
Frequency of HPV vaccination
A post-hoc analysis of the American Institute for Cancer Research CVT study showed that 1, 2, and 3 doses of 2vHPV were equally effective in preventing HPV infection, with 3 doses of vaccination providing at least partial prevention of HPV infection and related diseases, with an 80% reduction after completion of 3 doses of treatment.
WHO supports the use of 2-dose HPV vaccines to increase adherence and reduce the cost of HPV vaccination. Several countries such as Mexico and Chile also delayed the 3rd dose until 60 months prior to the WHO recommendation because the first 2 doses are so critical that the 3rd dose may not be necessary, and Mexico will begin a 2-dose vaccination program in 2015. The balance between effectiveness and frequency of vaccination still needs to be further explored.
Duration of HPV vaccination prophylactic protection
HPV-associated cancers tend to occur within the first 10 to 15 years after the onset of sexual activity, and the proportion of infections in older women continues to rise in association with the presence of persistent HPV infection or genotypic infection outside of the HPV vaccine. If HPV vaccination is administered at 5 years prior to median sexual initiation, protection is sustained for about 20 years to achieve maximum effectiveness. Available evidence suggests that experimental monovalent HPV16 vaccine, 2vHPV and 4vHPV vaccines induce sustained immune responses with significantly higher antibody titers than those induced by natural infection, with prevention of infection lasting 8-9 years, although of course clinical trials are unlikely to be followed up indefinitely all the time.
Side effects and safety of HPV vaccine
The Canadian Adverse Events after HPV Vaccination (AEFI) surveillance found the incidence to be 37.4/100,000, slightly lower than the 53.9/100,000 in the U.S. The main post-vaccination adverse effects were mental disorders (19.4%), digestive disorders (15.8%) and respiratory disorders (9.9%). One of the most serious complications within 42 days after immunization was venous thrombosis, which was monitored in Canada and occurred in 4 of 195,270 vaccinated individuals. However, whether there is a direct association between venous thrombosis and HPV vaccination events is controversial, and some experts believe that there is no direct link between HPV vaccination and the occurrence of venous thrombosis.
The WHO Global Committee on Vaccine Safety stated on March 12, 2014 that the GACVS will continue to closely monitor the safety of HPV vaccination and carefully evaluate the available evidence, and at this time still considers the benefit-risk ratio of HPV vaccination to be optimistic. The committee also highlighted an increase in incidents of vaccination side effects in recent years, but most are unconfirmed or lack evidence.
It is important to know that vaccination does not completely prevent the development of cervical cancer. 2- and 4-valent vaccines only immunize against the 2 most cancer-causing HPV high-risk types, HPV 16 and 18. These two HPV subtypes are associated with more than 75 percent of cervical cancers. However, although data show that the vaccine provides 100% of CINs caused by HPV 16 and 18 in previously uninfected women, another 30% of cervical cancers arise from other HPV high-risk subtypes not yet covered by the vaccine. 9-valent vaccine provides additional immunity to 5 additional high-risk types, but still does not cover all high-risk subtypes.
It is estimated that a significant decline in cervical cancer incidence will not occur until approximately 20 years after full vaccination. Until that date, cervical cancer screening remains the best method of preventing cervical cancer and screening recommendations are independent of HPV vaccination status. This means that although the HPV vaccine is an important step in cervical cancer prevention, it is not yet a substitute for routine cervical cancer screening.