HPV vaccine

HPV vaccine

Vaccine description
Target	Human papillomavirus (HPV)
Vaccine type	Protein subunit
Clinical data
Trade names	Gardasil, Cervarix, others
AHFS/Drugs.com	Monograph
MedlinePlus	a615028
License data	US DailyMed: Human_papillomavirus_vaccine
Pregnancy category	AU: B2
Routes of administration	Intramuscular injection
ATC code	J07BM01 (WHO) J07BM02 (WHO) J07BM03 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: Rx-only, Schedule D UK: POM (Prescription only) US: ℞-only EU: Rx-only
Identifiers
CAS Number	910046-32-1
ChemSpider	none
NY (what is this?)  (verify)

Human papillomavirus (HPV) vaccines are vaccines that prevent infection by certain types of human papillomavirus (HPV). Available HPV vaccines protect against either two, four, or nine types of HPV. All HPV vaccines protect against at least HPV types 16 and 18, which cause the greatest risk of cervical cancer. It is estimated that HPV vaccines may prevent 70% of cervical cancer, 80% of anal cancer, 60% of vaginal cancer, 40% of vulvar cancer, and show more than 90% efficacy in preventing HPV-positive oropharyngeal cancers. They additionally prevent some genital warts, with the quadrivalent and nonavalent vaccines that protect against HPV types HPV-6 and HPV-11 providing greater protection.

The World Health Organization (WHO) recommends HPV vaccines as part of routine vaccinations in all countries, along with other prevention measures. The vaccines require two or three doses depending on a person's age and immune status. Vaccinating girls around the ages of nine to thirteen is typically recommended. The vaccines provide protection for at least 5 to 10 years.Cervical cancer screening is still required following vaccination. Vaccinating a large portion of the population may also benefit the unvaccinated.

HPV vaccines are very safe. Pain at the site of injection occurs in about 80% of people. Redness and swelling at the site and fever may also occur. No link to Guillain–Barré syndrome has been found.

The first HPV vaccine became available in 2006. As of 2022, 125 countries include HPV vaccine in their routine vaccinations for girls, and 47 countries also for boys. It is on the World Health Organization's List of Essential Medicines and prequalified vaccines. Vaccination may be cost effective in the low and middle-income countries. As of 2017, Gardasil 9 is the only HPV vaccine available in the United States, as it provides protection against more HPV types than the earlier approved vaccines (the original Gardasil and Cervarix).

Medical uses

HPV vaccines are used to prevent HPV infection and therefore cervical cancer. Vaccinating females between the ages of nine to thirteen is typically recommended, with many countries also vaccinating males in that age range. In the United States, the CDC recommends that all 11- to 12-year-olds receive two doses of HPV vaccine, administered 6 to 12 months apart. The vaccines require three doses for those ages 15 and above. HPV vaccines are recommended in the United States for women and men who are 9–26 years of age, and are also approved for those who are 27–45 years of age.

HPV vaccination of large percentage of people within a population has been shown to decrease rates of HPV infections, with part of the benefit from herd immunity. Since the vaccines only cover some high-risk types of HPV, cervical cancer screening is recommended even after vaccination. In the U.S., the recommendation is for women to receive routine Pap smears beginning at age 21. In Australia, the national screening program has changed from the two yearly cytology (pap smears) to being based on tests for HPV DNA, based on work by Karen Canfell and others.

Efficacy

The HPV vaccine has been shown to prevent cervical dysplasia from the high-risk HPV types 16 and 18 and provide some protection against a few closely related high-risk HPV types. However, there are other high-risk HPV types that are not affected by the vaccine. The protection against HPV 16 and 18 has lasted at least eight years after vaccination for Gardasil and more than nine years for Cervarix. It is thought that booster vaccines will not be necessary.

Gardasil and Gardasil 9 protect against HPV types 6 and 11 which can cause genital warts.

Cervarix is just as effective at protecting women against persistent HPV 16 and 18 infection in the anus as it is at protecting them from these infections in the cervix. Overall, about 30 percent of cervical cancers will not be prevented by these vaccines. Also, in the case of Gardasil, ten percent of genital warts will not be prevented by the vaccine. Neither vaccine prevents other sexually transmitted diseases, nor do they treat existing HPV infection or cervical cancer.

HPV types 16, 18 and 45 contribute to 94% of cervical adenocarcinoma (cancers originating in the glandular cells of the cervix). While most cervical cancer arises in the squamous cells, adenocarcinomas make up a sizable minority of cancers. Further, Pap smears are not as effective at detecting adenocarcinomas, so where Pap screening programs are in place, a larger proportion of the remaining cancers are adenocarcinomas. Trials suggest that HPV vaccines may also reduce the incidence of adenocarcinoma.

Two doses of the vaccine may work as well as three doses. The Centers for Disease Control and Prevention (CDC) recommends two doses in those less than 15 years and three doses in those over 15 years. A single dose might be effective.

A study with 9vHPV, a 9-valent HPV vaccine that protects against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58, came to the result that the rate of high-grade cervical, vulvar, or vaginal disease was the same as when using a quadrivalent HPV vaccine. A lack of a difference may have been caused by the study design of including women 16 to 26 years of age, who may largely already have been infected with the five additional HPV types that are additionally covered by the 9-valent vaccine.

Males

HPV vaccines are approved for males in several countries and regions, including Switzerland, Portugal, Canada, Australia, Ireland, South Korea, Hong Kong, the United Kingdom, New Zealand, the Netherlands, and the United States.

In males, Gardasil may reduce their risk of genital warts and precancerous lesions caused by HPV. This reduction in precancerous lesions might be predicted to reduce the rates of penile and anal cancer in men. Gardasil has been shown to also be effective in preventing genital warts in males. While Gardasil and the Gardasil 9 vaccines have been approved for males, a third HPV vaccine, Cervarix, has not. Unlike the Gardasil-based vaccines, Cervarix does not protect against genital warts.

Since penile and anal cancers are much less common than cervical cancer, HPV vaccination of young men is likely to be much less cost-effective than for young women.

Gardasil is also used among men who have sex with men, who are at higher risk for genital warts, penile cancer, and anal cancer.

Recommendations by national bodies

Australia introduced HPV vaccination for boys over 12 from 2013 onwards, while UK and Ireland introduced HPV vaccination for boys aged 12 and 13 as part of their National Immunization Plan in 2019. Portugal introduced universal HPV vaccination for boys aged 10 years and above as part of its National Immunization Plan in 2020.

On 9 September 2009, an advisory panel recommended that the Food and Drug Administration (FDA) of the USA license Gardasil in the United States for boys and men ages 9–26 for the prevention of genital warts. Soon after that, the vaccine was approved by the FDA for use in males aged 9 to 26 for prevention of genital warts and anal cancer.

In 2011, an advisory panel for the Centers for Disease Control and Prevention (CDC) recommended the vaccine for boys ages 11–12. This was intended to prevent genital warts and anal cancers in males, and possibly prevent head and neck cancer (though the vaccine's effectiveness against head and neck cancers has not yet been proven). The committee also made the vaccination recommendation for males 13 to 21 years who have not been vaccinated previously or who have not completed the three-dose series. For those under the age of 27 who have not been fully vaccinated the CDC recommends vaccination.

Harald zur Hausen's support for vaccinating boys (so that they will be protected, and thereby so will women) was joined by professors Harald Moi and Ole-Erik Iversen in 2011.

Older age

When Gardasil was first introduced, it was recommended as a prevention for cervical cancer for women 25 years old or younger. Evidence suggests that HPV vaccines are effective in preventing cervical cancer for women up to 45 years of age. In 2018, the Food and Drug Administration released a summary basis for regulatory action and approval for expansion of usage and indication for the 9-valent HPV vaccine to include men and women 27 to 45 years of age.

Public health

The National Cancer Institute states "Widespread vaccination has the potential to reduce cervical cancer deaths around the world by as much as two-thirds if all women were to take the vaccine and if protection turns out to be long-term. In addition, the vaccines can reduce the need for medical care, biopsies, and invasive procedures associated with the follow-up from abnormal Pap tests, thus helping to reduce health care costs and anxieties related to abnormal Pap tests and follow-up procedures."

As of 2004 preventive vaccines protect against the two HPV types (16 and 18) that cause about 70% of cervical cancers worldwide. Because of the distribution of HPV types associated with cervical cancer, the vaccines are likely to be most effective in Asia, Europe, and North America. Some other high-risk types cause a larger percentage of cancers in other parts of the world. Vaccines that protect against more of the types common in cancers would prevent more cancers, and be less subject to regional variation. For instance, a vaccine against the seven types most common in cervical cancers (16, 18, 45, 31, 33, 52, 58) would prevent an estimated 87% of cervical cancers worldwide.

Only 41% of women with cervical cancer in the developing world get medical treatment. Therefore, prevention of HPV by vaccination may be a more effective way of lowering the disease burden in developing countries than cervical screening. The European Society of Gynecological Oncology sees the developing world as most likely to benefit from HPV vaccination. However, individuals in many resource-limited nations, Kenya for example, are unable to afford the vaccine.

In more developed countries, populations that do not receive adequate medical care, such as poor or minorities in the United States or parts of Europe also have less access to cervical screening and appropriate treatment, and are similarly more likely to benefit. In 2009, Dr. Diane Harper, a researcher for the HPV vaccines, questioned whether the benefits of the vaccine outweigh its risks in countries where Pap smear screening is common. She has also encouraged women to continue pap screening after they are vaccinated and to be aware of potential adverse effects.

According to the CDC, in 2012, use of the HPV vaccine had cut rates of infection with HPV-6, -11, -16 and -18 in half in American teenagers (from 11.5% to 4.3%) and by one third in American women in their early twenties (from 18.5% to 12.1%).

Side effects

The HPV vaccine is generally safe with no increased risk of serious adverse effects. HPV vaccines are approved for use in over 100 countries, with more than 100 million doses distributed worldwide. Extensive clinical trial and post-marketing safety surveillance data indicate that both Gardasil and Cervarix are well tolerated and safe. When comparing the HPV vaccine to a placebo (control) vaccine taken by women, there is no difference in the risk of severe adverse events.

Gardasil is a three-dose (injection) vaccine. As of 8 September 2013, there were more than 57 million doses distributed in the United States, though it is unknown how many were administered. There have been 22,000 Vaccine Adverse Event Reporting System (VAERS) reports following the vaccination. 92% were reports of events considered to be non-serious (e.g., fainting, pain and swelling at the injection site (arm), headache, nausea and fever), and the rest were considered to be serious (death, permanent disability, life-threatening illness and hospitalization). However, VAERS reports include any reported effects whether coincidental or causal. In response to concerns regarding the rates of adverse events associated with the vaccine, the CDC stated: "When evaluating data from VAERS, it is important to note that for any reported event, no cause-and-effect relationship has been established. VAERS receives reports on all potential associations between vaccines and adverse events."

As of 1 September 2009, in the US there were 44 reports of death in females after receiving the vaccine. None of the 27 confirmed deaths of women and girls who had taken the vaccine were linked to the vaccine. There is no evidence suggesting that Gardasil causes or raises the risk of Guillain–Barré syndrome. Additionally, there have been rare reports of blood clots forming in the heart, lungs, and legs. A 2015 review conducted by the European Medicines Agency's Pharmacovigilance Risk Assessment Committee concluded that evidence does not support the idea that HPV vaccination causes complex regional pain syndrome or postural orthostatic tachycardia syndrome.

As of 8 September 2013, the CDC continued to recommend Gardasil vaccination for the prevention of four types of HPV. The manufacturer of Gardasil has committed to ongoing research assessing the vaccine's safety.

According to the Centers for Disease Control and Prevention (CDC) and the FDA, the rate of adverse side effects related to Gardasil immunization in the safety review was consistent with what has been seen in the safety studies carried out before the vaccine was approved and were similar to those seen with other vaccines. However, a higher proportion of syncope (fainting) was seen with Gardasil than is usually seen with other vaccines. The FDA and CDC have reminded health care providers that, to prevent falls and injuries, all vaccine recipients should remain seated or lying down and be closely observed for 15 minutes after vaccination. The HPV vaccination does not appear to reduce the willingness of women to undergo pap tests.

Contraindications

While the use of HPV vaccines can help reduce cervical cancer deaths by two-thirds around the world, not everyone is eligible for vaccination. There are some factors that exclude people from receiving HPV vaccines. These factors include:

• People with history of immediate hypersensitivity to vaccine components. Patients with a hypersensitivity to yeast should not receive Gardasil since yeast is used in its production.
• People with moderate or severe acute illnesses. This does not completely exclude patients from vaccination, but postpones the time of vaccination until the illness has improved.

Pregnancy

In the Gardasil clinical trials, 1,115 pregnant women received the HPV vaccine. Overall, the proportions of pregnancies with an adverse outcome were comparable in subjects who received Gardasil and subjects who received placebo. However, the clinical trials had a relatively small sample size. As of 2018, the vaccine is not recommended for pregnant women.

The FDA has classified the HPV vaccine as a pregnancy Category B, meaning there is no apparent harm to the fetus in animal studies. HPV vaccines have not been causally related with adverse pregnancy outcomes or adverse effects on the fetus. However, data on vaccination during pregnancy is very limited and vaccination during the pregnancy term should be delayed until more information is available. If a woman is found to be pregnant during the three-dose series of vaccination, the series should be postponed until pregnancy has been completed. While there is no indication for intervention for vaccine dosages administered during pregnancy, patients and healthcare providers are encouraged to report exposure to vaccines to the appropriate HPV vaccine pregnancy registry.

Mechanism of action

The HPV vaccines are based on hollow virus-like particles (VLPs) assembled from recombinant HPV coat proteins. The natural virus capsid is composed of two proteins, L1 and L2, but vaccines only contain L1.

Gardasil contains inactive L1 proteins from four different HPV strains: 6, 11, 16, and 18, synthesized in the yeast Saccharomyces cerevisiae. Each vaccine dose contains 225 µg of aluminum, 9.56 mg of sodium chloride, 0.78 mg of L-histidine, 50 µg of polysorbate 80, 35 µg of sodium borate, and water. The combination of ingredients totals 0.5 mL. HPV types 16 and 18 cause about 70% of all cervical cancer. Gardasil also targets HPV types 6 and 11, which together cause about 90 percent of all cases of genital warts.

Gardasil and Cervarix are designed to elicit virus-neutralizing antibody responses that prevent initial infection with the HPV types represented in the vaccine. The vaccines have been shown to offer 100 percent protection against the development of cervical pre-cancers and genital warts caused by the HPV types in the vaccine, with few or no side effects. The protective effects of the vaccine are expected to last a minimum of 4.5 years after the initial vaccination.

While the study period was not long enough for cervical cancer to develop, the prevention of these cervical precancerous lesions (or dysplasias) is believed highly likely to result in the prevention of those cancers.

History

The vaccine was first developed by the University of Queensland in Australia and the final form was made by researchers at the University of Queensland, Georgetown University Medical Center, University of Rochester, and the U.S. National Cancer Institute. Researchers Ian Frazer and Jian Zhou at the University of Queensland have been accorded priority under U.S. patent law for the invention of the HPV vaccine's basis, the VLPs. In 2006, the FDA approved the first preventive HPV vaccine, marketed by Merck & Co. under the trade name Gardasil. According to a Merck press release, by the second quarter of 2007 it had been approved in 80 countries, many under fast-track or expedited review. Early in 2007, GlaxoSmithKline filed for approval in the United States for a similar preventive HPV vaccine, known as Cervarix. In June 2007, this vaccine was licensed in Australia, and it was approved in the European Union in September 2007. Cervarix was approved for use in the U.S. in October 2009.

Harald zur Hausen, a German researcher who suspected, and later helped to prove that genital HPV infection can lead to cervical cancer, was awarded half of the $1.4 million Nobel Prize in Medicine in 2008 for his work. Verification that cervical cancer is caused by an infectious agent led several other groups to develop vaccines against HPV strains that cause most cases of cervical cancer. The other half of the award went to Françoise Barré-Sinoussi and Luc Montagnier, two French virologists, for their part in the discovery of HIV.

Harald zur Hausen was skeptical of the prevailing dogma and postulated that oncogenic human papilloma virus (HPV) caused cervical cancer. He realized that HPV-DNA could exist in an inactive state in the tumours, and should be detectable by specific searches for viral DNA. He and workers at the Pasteur Institute found HPV to be a heterogeneous family of viruses. Only some HPV types cause cancer.

Harald zur Hausen pursued his research for over ten years searching for different HPV types. This research was difficult because only parts of the viral DNA were integrated into the host genome. He found novel HPV-DNA in cervix cancer biopsies, and thus discovered the new, tumourigenic HPV16 type in 1983. In 1984, he cloned HPV16 and 18 from patients with cervical cancer. The HPV types 16 and 18 were consistently found in about 70% of cervical cancer biopsies throughout the world.

His observation of HPV oncogenic potential in human malignancy provided impetus within the research community to characterize the natural history of HPV infection, and to develop a better understanding of mechanisms of HPV-induced carcinogenesis.

In December 2014, the US Food and Drug Administration (FDA) approved a vaccine called Gardasil 9 to protect females between the ages of 9 and 26 and males between the ages of 9 and 15 against nine strains of HPV. Gardasil 9 protects against infection from the strains covered by the first generation of Gardasil (HPV-6, HPV-11, HPV-16, and HPV-18) and protects against five other HPV strains responsible for 20% of cervical cancers (HPV-31, HPV-33, HPV-45, HPV-52, and HPV-58).

Society and culture

Cost

As of 2013, vaccinating girls and young women was estimated to be cost-effective in the low and middle-income countries, especially in places without organized programs for screening cervical cancer. When the cost of the vaccine itself, or the cost of administering it to individuals, were higher, or if cervical cancer screening were readily available, then vaccination was less likely to be cost-effective.

From a public health point of view, vaccinating men as well as women decreases the virus pool within the population, but is only cost-effective to vaccinate men when the uptake in the female population is extremely low. In the United States, the cost per quality-adjusted life year is greater than US$100,000 for vaccinating the male population, compared to the less than US$50,000 for vaccinating the female population. This assumes a 75% vaccination rate.

In 2013, the two companies who sell the most common vaccines announced a price cut to less than US$5 per dose to poor countries, as opposed to US$130 per dose in the U.S.

Vaccine implementation

In developed countries, the widespread use of cervical "Pap smear" screening programs has reduced the incidence of invasive cervical cancer by 50% or more. Preventive vaccines reduce but do not eliminate the chance of getting cervical cancer. Therefore, experts recommend that women combine the benefits of both programs by seeking regular Pap smear screening, even after vaccination. School-entry vaccination requirements were found to increase the use of the HPV vaccine.

Due to the COVID-19 pandemic (2019–2021), HPV vaccination programs have been significantly affected in the United States, low-income and lower-middle income countries. On 30 August 2021, fifteen leading academic and freestanding cancer centers with membership in the Association of American Cancer Institutes (AACI), all National Cancer Institute (NCI)-designated cancer centers, the American Cancer Society, the American Society of Clinical Oncology, the American Association for Cancer Research, and the St. Jude Children's Research Hospital have issued a joint statement urging the U.S. health care systems, physicians, parents, children and young adults to get HPV vaccination and other recommended vaccinations back on track during the National Immunization Awareness Month.

Africa

With support from the GAVI Alliance, a number of low-income African countries have begun rollout of the HPV vaccine, with others to follow. In 2013 Ghana, Kenya, Madagascar, Malawi, Niger, Sierra Leone, and the United Republic of Tanzania begin implementation of the vaccine. In 2014, Rwanda will begin nationwide rollout, and demonstration programs will take place in Mozambique and Zimbabwe.

Australia

In April 2007, Australia became the second country—after Austria—to introduce a government-funded National Human Papillomavirus (HPV) Vaccination Program to protect young women against HPV infections that can lead to cancers and disease. The National HPV Vaccination Program is listed on the National Immunisation Program (NIP) Schedule and funded under the Immunise Australia Program. The Immunise Australia Program is a joint Federal, State, and Territory Government initiative to increase immunisation rates for vaccine-preventable diseases.

The National HPV Vaccination Program for females was made up of two components: an ongoing school-based program for 12- and 13-year-old girls; and a time-limited catch-up program (females aged 14–26 years) delivered through schools, general practices, and community immunization services, which ceased on 31 December 2009.

During 2007–2009, an estimated 83% of females aged 12–17 years received at least one dose of HPV vaccine and 70% completed the 3-dose HPV vaccination course. By 2017, HPV coverage data on the Immunise Australia website show that by 15 years of age, over 82% of Australian females had received all three doses.

Since the National HPV Vaccination Program commenced in 2007, there has been a reduction in HPV-related infections in young women. A study published in The Journal of Infectious Diseases in October 2012 found the prevalence of vaccine-preventable HPV types (6, 11, 16 and 18) in Papanicolaou test results of women aged 18–24 years has significantly decreased from 28.7% to 6.7% four years after the introduction of the National HPV Vaccination Program. A 2011 report published found the diagnosis of genital warts (caused by HPV types 6 and 11) had also decreased in young women and men.

In October 2010, the Australian regulatory agency, the Therapeutic Goods Administration, extended the registration of the quadrivalent vaccine (Gardasil) to include use in males aged 9 through 26 years of age, for the prevention of external genital lesions and infection with HPV types 6, 11, 16 and 18.

In November 2011, the Pharmaceutical Benefits Advisory Committee (PBAC) recommended the extension of the National HPV Vaccination Program to include males. The PBAC made its recommendation on the preventive health benefits that can be achieved, such as a reduction in the incidence of anal and penile cancers and other HPV-related diseases. In addition to the direct benefit to males, it was estimated that routine HPV vaccination of adolescent males would contribute to the reduction of vaccine HPV-type infection and associated disease in women through herd immunity.

In 2012, the Australian Government announced it would be extending the National HPV Vaccination Program to include males, through the National Immunisation Program Schedule.

Updated results were reported in 2014.

From February 2013, free HPV vaccine is being provided through school-based programs for:

• males and females aged 12–13 years (ongoing program); and
• males aged between 14 and 15 years – until the end of the school year in 2014 (catch up program).

Canada

HPV vaccines were first approved in Canada in July 2006 for use in females, and February 2010 for use in males.

The vaccines Cervarix, Gardasil, and Gardasil 9 are authorized for use in Canada, with Gardasil 9 the primary vaccine used. All provinces and territories (except Quebec) administer Gardasil 9 on a two or three dose schedule: individuals under age 15 are given two doses, while individuals who are immunocompromised, living with HIV, or age 15+ are given three doses. Quebec provides two doses to individuals under 18 years (the first dose is Gardasil 9, and the second dose is Cervarix) and three doses of Gardasil 9 to people age 18+.

The administration of free vaccination programs is provided by individual province and territory governments. All provincial and territorial governments offer free vaccination for school-aged children, irrespective of gender. The school grades in which the vaccine is provided varies by province and territory: grade 4 and secondary 3 (Quebec); grade 6 (British Columbia, Manitoba, Newfoundland and Labrador, Nunavut, Prince Edward Island, Saskatchewan, Yukon); grades 6 and 9 (Alberta); grades 4-6 (Northwest Territories); or grade 7 (New Brunswick, Nova Scotia, Ontario). Publicly funded HPV vaccines are also provided in certain provinces and territories for other groups of people, such as men who have sex with men, individuals living with HIV, and individuals who identify as transgender. Individuals who do not qualify for any of the publicly-funded programs can privately purchase the three-dose HPV vaccine series for $510 to $630.

China

GlaxoSmithKline China announced in 2016, that Cervarix (HPV vaccine 16 and 18) had been approved by the China Food and Drug Administration (CFDA). Cervarix is registered in China for girls aged 9 to 45, adopting 3-dose program within 6 months. Cervarix was launched in China in 2017, and it was the first approved HPV vaccine in China.

Colombia

The vaccine was introduced in 2012, approved for girls aged 9. The HPV vaccine was initially offered to girls aged 9 and older, and attending the fourth grade of school. Since 2013 the age of coverage was extended to girls in school from grade four (who have reached the age of 9) to grade eleven (independent of age); and no schooling from age 9–17 years 11 months and 29 days old.

Costa Rica

Since June 2019, the vaccine is administered compulsorily by the state, free of charge to girls at ten years of age.

Europe

Country	Date of introduction	Gender(s)	Target age group	Financed by	Policy
Austria	2006	M/F	10–12	Fully financed by national health authorities for everyone age 9 to 20 years	Voluntary immunization
Belgium	2007	F	10–13	Fully financed by national health authorities	Mandatory; part of the national immunization schedule
Croatia	20 May 2016	M/F	12	Fully financed by national health authorities	Voluntary immunization for women not yet sexually active
Denmark	1 January 2009	M/F	12	Fully financed by national health authorities	Part of the Danish Childhood Vaccination program
Finland	21 November 2013 for female, 20 May 2020 for male	M/F	11–12	Fully financed by national health authorities	Part of the Finnish National Vaccination program
France	11 July 2007	F	14–23	Financed 65% by national health authorities	Voluntary immunization for women not yet sexually active
Germany	26 March 2007	M/F	9–14	Fully financed by mandatory health insurance	Voluntary immunization
Greece	12 February 2007	F	12–26	Fully financed by national health authorities	Mandatory for all girls entering 7th grade
Hungary	2014	M/F	12	Fully financed by national health authorities. In addition subsidised by local councils for 13- and 14-year-olds.
Iceland	2011		12	Fully financed by national health authorities
Ireland	2009	M/F	12–13	Fully financed by national health authorities	Offered to males and female in first year of secondary school. Non-mandatory. HPV vaccination introduced to national immunisation scheme for males in 2019.
Italy	26 March 2007	M/F	12	Fully financed by national health authorities initially for girls only. Offered to boys from 2017.
Latvia	2009		12	Fully financed by national health authorities
Luxembourg	2008		12	Fully financed by national health authorities
Netherlands	2009	F	12–13	Fully financed by national health authorities
North Macedonia	2009	F	12	Fully financed by national health authorities	Mandatory; part of the national immunization schedule
Norway	2009	F	12–13		Part of the national immunization program
Portugal	2007	F	13	Fully financed by national health authorities	Part of the national immunization program for both boys and girls
Romania	November 2008	F	10-18	Fully financed by national health authorities	Part of the national immunization program, but not mandatory for 10–14 years old girls until August 2021, up to 18 years old as of 3 September 2021
Slovenia	2009		11–12	Fully financed by national health authorities
Spain	2007		11–14	Fully financed by national health authorities
Sweden	2012	M/F	10–11	The school-based vaccination program is fully financed by national health authorities, initially for girls only. Offered to all children in fifth grade from August 2020 (boys born 2009 are included).	All vaccinations within the national vaccination programme for children are voluntary.
Switzerland	2008		11–14	Fully financed by national health authorities
UK	September 2008	M/F	M: 9–45 F: 9–45	Fully financed by national health authorities initially for girls only. Offered to boys aged 12 and 13 years from September 2019. The HPV vaccine is available for free on the NHS up until a person's 25th birthday if they were eligible and missed the HPV vaccine offered in Year 8 at school,: girls born after 1 September 1991 boys born after 1 September 2006 Also fully financed by national health authorities since 2018 for men aged up to and including 45 years of age who have sex with other men (MSM) when they visit sexual health clinics and HIV clinics in England. Trans women (people who were assigned male at birth) are eligible in the same way as MSM if their risk of getting HPV is similar to the risk of MSM who are eligible for the HPV vaccine. Trans men (people who were assigned female at birth) are eligible if they have sex with other men and are aged 45 or under.	Offered to males and female in second year of secondary school, as well as at sexual health and HIV clinics in England. Non-mandatory.

Hong Kong

HPV vaccines are approved for use in Hong Kong. As part of the Hong Kong Childhood Immunisation Programme, HPV vaccines became mandatory for students in the 2019/2020 school year, exclusively for females at primary 5 and 6 levels.

India

HPV vaccination has been recommended by the National Technical Advisory Group on Immunization, but has not been implemented in India as of 2018.

Ireland

The HPV vaccination programme in Ireland is part of the national strategy to protect females from cervical cancer. Since 2009, the Health Service Executive has offered the HPV vaccine, free of charge, to all girls from first year onwards (ages 12–13). Secondary schools began implementing the vaccine program on an annual basis from September 2010 onwards. The programme was expanded to include males in 2019. Two HPV vaccines are licensed for use in Ireland: Cervarix and Gardasil. To ensure high uptake, the vaccine is administered to teenagers aged 12–13 in their first year of secondary school, with the first dose administered between September–October and the final dose in April of the following year. Males and females aged 12–13 who are outside of the traditional school setting (home school, etc.) are invited to Health service Executive clinics for their vaccines. HPV vaccination in Ireland in not mandatory and consent is obtained prior to vaccination. For males and females aged 16 and under, consent is granted by a parent or guardian, unless it is explicitly refused by the child. Any male or female aged 16 and over may provide their own consent if they want to be vaccinated.HIQA has stated the vaccine will provide further protection, particularly to men who have sex with men. The vaccine has been extended following evidence that 25% of HPV cancers occur in men. Additionally, HIQA is aiming to replace the current vaccination, which covers 4 major HPV strains, with an updated vaccine providing protection from 9 strains. The over cost with the "gender-neutral nine-talent" vaccine is estimated to be nearly €11.66 million over the next five years.

Israel

Introduced in 2012. Target age group 13–14. Fully financed by national health authorities only for this age group. For the year 2013–2014, girls in the eighth grade may get the vaccine free of charge only in school, and not in Ministry of Health offices or clinics. Girls in the ninth grade may receive the vaccine free of charge only at Ministry of Health offices, and not in schools or clinics. Religious and conservative groups are expected to refuse the vaccination.

Japan

Introduced in 2010, widely available only since April 2013. Fully financed by national health authorities to females aged 11 to 16 years. In June 2013, however, Japan's Vaccine Adverse Reactions Review Committee (VARRC) suspended recommendation of the vaccine due to fears of adverse events. This directive has been criticized by researchers at the University of Tokyo as a failure of governance since the decision was taken without presentation of adequate scientific evidence. At the time, Ministry spokespeople emphasized that "The decision does not mean that the vaccine itself is problematic from the viewpoint of safety," but that they wanted time to conduct analyses on possible adverse effects, "to offer information that can make the people feel more at ease." However, the suspension of the Ministry's endorsement was still in place as of February 2019, by which time the HPV vaccination rate among younger women fell from approximately 70% in 2013 to 1% or less. Over an overlapping time period (2009–2019), the age-adjusted mortality rate from cervical cancer increased by 9.6%. Japan to Resume Active Promotion of HPV Vaccinations in April 2022. In December 2021, the Ministry of Health, Labour and Welfare has decided to allow free vaccines to women born between fiscal year 1997 and 2005 after eight-year hiatus. A panel of Japan's Ministry of Health, Labour and Welfare agreed to give women (born between fiscal 1997 and fiscal 2005), free vaccinations, if they missed the country's free vaccination program.

Kenya

Both Cervarix and Gardasil are approved for use within Kenya by the Pharmacy and Poisons Board. However, at a cost of 20,000 Kenyan shillings, which is more than the average annual income for a family, the director of health promotion in the Ministry of Health, Nicholas Muraguri, states that many Kenyans are unable to afford the vaccine.

Laos

In 2013, Laos began implementation of the HPV vaccine, with the assistance of the Gavi Alliance.

Mexico

The vaccine was introduced in 2008 to 5% of the population. This percentage of the population had the lowest development index which correlates with the highest incidence of cervical cancer. The HPV vaccine is delivered to girls 12 – 16 years old following the 0-2-6 dosing schedule. By 2009 Mexico had expanded the vaccine use to girls, 9–12 years of age, the dosing schedule in this group was different, the time elapsed between the first and second dose was six months and the third dose 60 months later. In 2011 Mexico approved a nationwide use of HPV vaccination program to include vaccination of all 9-year-old girls.

New Zealand

Immunization as of 2017 is free for males and females aged 9 to 26 years.

The public funding began on 1 September 2008. The vaccine was initially offered only to girls, usually through a school-based program in Year 8 (approximately age 12), but also through general practices and some family planning clinics. Over 200,000 New Zealand girls and young women have received HPV immunization.

Panama

The vaccine was added to the national immunization program in 2008, to target 10-year-old girls.

South Africa

Cervical cancer represents the most common cause of cancer-related deaths—more than 3,000 deaths per year—among women in South Africa because of high HIV prevalence, making introduction of the vaccine highly desirable. A Papanicolaou test program was established in 2000 to help screen for cervical cancer, but since this program has not been implemented widely, vaccination would offer more efficient form of prevention. In May 2013 the Minister of Health of South Africa, Aaron Motsoaledi, announced the government would provide free HPV vaccines for girls aged 9 and 10 in the poorest 80% of schools starting in February 2014 and the fifth quintile later on. South Africa will be the first African country with an immunisation schedule that includes vaccines to protect people from HPV infection, but because the effectiveness of the vaccines in women who later become infected with HIV is not yet fully understood, it is difficult to assess how cost-effective the vaccine will be. Negotiations are currently underway for more affordable HPV vaccines since they are up to 10 times more expensive than others already included in the immunization schedule.

South Korea

On 27 July 2007, South Korean government approved Gardasil for use in girls and women aged 9 to 26 and boys aged 9 to 15. Approval for use in boys was based on safety and immunogenicity but not efficacy.

Since 2016, HPV vaccination has been part of the National Immunization Program, offered free of charge to all children under 12 in South Korea, with costs fully covered by the Korean government.

For 2016 only, Korean girls born between 1 January 2003 and 31 December 2004 were also eligible to receive the free vaccinations as a limited time offer. From 2017, the free vaccines are available to those under 12 only.

Trinidad and Tobago

Introduced in 2013. Target Group 9–26. Fully financed by national health authorities. But was suspended later on that year owing to objections and concerns raised by the Catholic Board, but fully available in local health centers.

United Arab Emirates

The World Health Organization ranks cervical cancer as the fourth most frequent cancer among women in UAE, at 7.4 per 100,000 women, and according to Abu Dhabi Health Authority, the cancer is also the seventh highest cause of death of women in the U.A.E.

In 2007, the HPV vaccine was approved for girls and young women, 15 to 26 years of age, and offered optionally at hospitals and clinics. Moreover, starting 1 June 2013, the vaccine was offered free of charge for women between the ages of 18 and 26, in Abu Dhabi. However, on 14 September 2018, the U.A.E's Ministry of Health and Community Protection announced that HPV vaccine became a mandatory part of the routine vaccinations for all girls in the U.A.E. The vaccine is to be administers to all school girls in the 8th grade girls, aged 13.

United Kingdom

In the UK the vaccine is licensed for females aged 9–26, for males aged 9–15, and for men who have sex with men aged 18–45.

HPV vaccination was introduced into the national immunisation programme in September 2008, for girls aged 12–13 across the UK. A two-year catch-up campaign started in Autumn 2009 to vaccinate all girls up to 18 years of age. Catch up vaccination was offered to girls aged between 16 and 18 from autumn 2009, and girls aged between 15 and 17 from autumn 2010. It will be many years before the vaccination programme has an effect on cervical cancer incidence so women are advised to continue accepting their invitations for cervical screening.Men who have sex with men up to and including the age of 45 became eligible for free HPV vaccination on the NHS in April 2018. They get the vaccine by visiting sexual health clinics and HIV clinics in England. A meta-analysis of vaccinations for men who have sex with men showed that this strategy is most effective when combined with gender-neutral vaccination of all boys, regardeless of their sexual orientation.

From the 2019/2020 school year, it is expected that 12- to 13-year-old boys will also become eligible for the HPV vaccine as part of the national immunisation programme. This follows a statement by the Joint Committee on Vaccination and Immunisation. The first dose of the HPV vaccine will be offered routinely to boys aged 12 and 13 in school year 8, in the same way that it is currently (May 2018) offered to girls.Boots UK had opened a private HPV vaccination service to boys and men aged 12–44 years in April 2017 at a cost of £150 per vaccination. In children aged 12–14 years two doses are recommended, while those aged 15–44 years a course of three is recommended.

Cervarix was the HPV vaccine offered from introduction in September 2008, to August 2012, with Gardasil being offered from September 2012. The change was motivated by Gardasil's added protection against genital warts.

United States

Adoption

As of late 2007, about one quarter of U.S. females age 13–17 years had received at least one of the three HPV shots. By 2014, the proportion of such females receiving an HPV vaccination had risen to 38%. The government began recommending vaccination for boys in 2011; by 2014, the vaccination rate among boys (at least one dose) had reached 35%.

According to the U.S. Centers for Disease Control and Prevention (CDC), getting as many girls vaccinated as early and as quickly as possible will reduce the cases of cervical cancer among middle-aged women in 30 to 40 years and reduce the transmission of this highly communicable infection. Barriers include the limited understanding by many people that HPV causes cervical cancer, the difficulty of getting pre-teens and teens into the doctor's office to get a shot, and the high cost of the vaccine ($120/dose, $360 total for the three required doses, plus the cost of doctor visits). Community-based interventions can increase the uptake of HPV vaccination among adolescents.

A survey was conducted in 2009 to gather information about knowledge and adoption of the HPV vaccine. Thirty percent of 13- to 17-year-olds and 9% of 18- to 26-year-olds out of the total 1,011 young women surveyed reported receipt of at least one HPV injection. Knowledge about HPV varied; however, 5% or fewer subjects believed that the HPV vaccine precluded the need for regular cervical cancer screening or safe-sex practices. Few girls and young women overestimate the protection provided by the vaccine. Despite moderate uptake, many females at risk of acquiring HPV have not yet received the vaccine. For example, young black women are less likely to receive HPV vaccines compared to young white women. Additionally, young women of all races and ethnicities without health insurance are less likely to get vaccinated.

Since the approval of Gardasil in 2006 and despite low vaccine uptake, prevalence of HPV among teenagers aged 14–19 has been cut in half with an 88% reduction among vaccinated women. No decline in prevalence was observed in other age groups, indicating the vaccine to have been responsible for the sharp decline in cases. The drop in number of infections is expected to in turn lead to a decline in cervical and other HPV-related cancers in the future.

Legislation

Four states have laws that require HPV vaccination for school students:Hawaii, Rhode Island, Virginia, and Washington D.C. Students in those states must have started HPV vaccination before entering the 7th grade. All school immunization laws grant exemptions to children for medical reasons, with other "opt-out" policies varying by state.

Shortly after the first HPV vaccine was approved, bills to make the vaccine mandatory for school attendance were introduced in many states. Only two such bills passed (in Virginia and Washington DC) during the first four years after vaccine introduction. Mandates have been effective at increasing uptake of other vaccines, such as mumps, measles, rubella, and hepatitis B (which is also sexually transmitted). However most such efforts developed for five or more years after vaccine release, while financing and supply were arranged, further safety data was gathered, and education efforts increased understanding, before mandates were considered. Most public policies including school mandates have not been effective in promoting HPV vaccination while receiving a recommendation from a physician increased the probability of vaccination.

In July 2015, Rhode Island added an HPV vaccine requirement for admittance into public school. This mandate requires all students entering the seventh grade to receive at least one dose of the HPV vaccine starting in August 2015, all students entering the eighth grade to receive at least two doses of the HPV vaccine starting in August 2016, and all students entering the ninth grade to receive at least three doses of the HPV vaccine starting in August 2017. No legislative action is required for the Rhode Island Department of Health to add new vaccine mandates. Rhode Island is the only state that requires the vaccine for both male and female 7th graders.

Immigrants

Between July 2008 and December 2009, proof of the first of three doses of HPV Gardasil vaccine was required for women ages 11–26 intending to legally enter the United States. This requirement stirred controversy because of the cost of the vaccine, and because all the other vaccines so required prevent diseases which are spread by respiratory route and considered highly contagious. The Centers for Disease Control and Prevention repealed all HPV vaccination directives for immigrants effective 14 December 2009. Uptake in the United States appears to vary by ethnicity and whether someone was born outside the United States.

Coverage

Measures have been considered including requiring insurers to cover HPV vaccination, and funding HPV vaccines for those without insurance. The cost of the HPV vaccines for females under 18 who are uninsured is covered under the federal Vaccines for Children Program. As of 23 September 2010, vaccines are required to be covered by insurers under the Patient Protection and Affordable Care Act. HPV vaccines specifically are to be covered at no charge for women, including those who are pregnant or nursing.

Medicaid covers HPV vaccination in accordance with the ACIP recommendations, and immunizations are a mandatory service under Medicaid for eligible individuals under age 21. In addition, Medicaid includes the Vaccines for Children Program. This program provides immunization services for children 18 and under who are Medicaid eligible, uninsured, underinsured, receiving immunizations through a Federally Qualified Health Center or Rural Health Clinic, or are Native American or Alaska Native.

The vaccine manufacturers also offer help for people who cannot afford HPV vaccination. GlaxoSmithKline's Vaccines Access Program provides Cervarix free of charge 1-877-VACC-911 to low income women, ages 19 to 25, who do not have insurance.Merck's Vaccine Patient Assistance Program 1-800-293-3881 provides Gardasil free to low income women and men, ages 19 to 26, who do not have insurance, including immigrants who are legal residents.

Opposition in the United States

The idea that the HPV vaccine is linked to increased sexual behavior is not supported by scientific evidence. A review of nearly 1,400 adolescent girls found no difference in teen pregnancy, incidence of sexually transmitted infection, or contraceptive counseling regardless of whether they received the HPV vaccine. Thousands of Americans die each year from cancers preventable by the vaccine. A disproportionate rate of HPV-related cancers exists amongst LatinX populations, leading researchers to explore how communication and messaging can be adjusted to address vaccine hesitancy.

Insurance companies

There has been significant opposition from health insurance companies to covering the cost of the vaccine ($360).

Religious and conservative groups

Opposition due to the safety of the vaccine has been addressed through studies, leaving opposition focused on the sexual implications of the vaccine to remain. Conservative groups in the U.S. have opposed the concept of making HPV vaccination mandatory for pre-adolescent girls, claiming that making the vaccine mandatory is a violation of parental rights and that it will give a false sense of immunity to sexually transmitted disease, leading to early sexual activity. (See Peltzman effect) Both the Family Research Council and the group Focus on the Family support widespread (universal) availability of HPV vaccines but oppose mandatory HPV vaccinations for entry to public school. Parents also express confusion over recent mandates for entry to public school, pointing out that HPV is transmitted through sexual contact, not through attending school with other children.

Conservative groups are concerned children will see the vaccine as a safeguard against STDs and will have sex sooner than they would without the vaccine while failing to use contraceptives. However, the American Academy of Pediatrics disagreed with the argument that the vaccine increases sexual activity among teens. Christine Peterson, director of the University of Virginia's Gynecology Clinic, said "The presence of seat belts in cars doesn't cause people to drive less safely. The presence of a vaccine in a person's body doesn't cause them to engage in risk-taking behavior they would not otherwise engage in." A 2018 study of college-aged students found that HPV vaccination did not increase sexual activity.

Parental opposition

Many parents opposed to providing the HPV vaccine to their pre-teens agree the vaccine is safe and effective, but find talking to their children about sex uncomfortable. Elizabeth Lange, of Waterman Pediatrics in Providence, RI, addresses this concern by emphasizing what the vaccine is doing for the child. Lange suggests parents should focus on the cancer prevention aspect without being distracted by words like 'sexually transmitted'. Everyone wants cancer prevention, yet here parents are denying their children a form of protection due to the nature of the cancer—Lange suggests that this much controversy would not surround a breast cancer or colon cancer vaccine. The HPV vaccine is suggested for 11-year-olds because it should be administered before possible exposure to HPV, but also because the immune system has the highest response for creating antibodies around this age. Lange also emphasized the studies showing that the HPV vaccine does not cause children to be more promiscuous than they would be without the vaccine.

Controversy over the HPV vaccine remains present in the media. Parents in Rhode Island have created a Facebook group called "Rhode Islanders Against Mandated HPV Vaccinations" in response to Rhode Island's mandate that males and females entering the 7th grade, as of September 2015, be vaccinated for HPV before attending public school.

Physician impact

The effectiveness of a physician's recommendation for the HPV vaccine also contributes to low vaccination rates and controversy surrounding the vaccine. A 2015 study of national physician communication and support for the HPV vaccine found physicians routinely recommend HPV vaccines less strongly than they recommend Tdap or meningitis vaccines, find the discussion about HPV to be long and burdensome, and discuss the HPV vaccine last, after all other vaccines. Researchers suggest these factors discourage patients and parents from setting up timely HPV vaccines. In order to increase vaccination rates, this issue must be addressed and physicians should be better trained to handle discussing the importance of the HPV vaccine with patients and their families.

Ethics

Some researchers have compared the need for adolescent HPV vaccination to that of other childhood diseases such as chicken pox, measles, and mumps. This is because vaccination before infection decreases the risk of a number of forms of cancer.

There has been some controversy around the HPV vaccine's rollout and distribution. Countries have taken different routes based on economics and social climate leading to issues of forced vaccination and marginalization of segments of the population in some cases.

The rollout of a country's vaccination program is more divisive, compared to the act of providing vaccination against HPV. In more affluent countries, arguments have been made for publicly funded programs aimed at vaccinating all adolescents voluntarily. These arguments are supported by World Health Organization (WHO) surveys showing the effectiveness of cervical cancer prevention with HPV vaccination.

In developing countries, cost of the vaccine, dosing schedule, and other factors have led to suboptimal levels of vaccination. Future research is focused on low-cost generics and single-dose vaccination in efforts to make the vaccine more accessible.

Research

There are high-risk HPV types, that are not affected by available vaccines. Ongoing research is focused on the development of HPV vaccines that will offer protection against a broader range of HPV types. One such method is a vaccine based on the minor capsid protein L2, which is highly conserved across HPV genotypes. Efforts for this have included boosting the immunogenicity of L2 by linking together short amino acid sequences of L2 from different oncogenic HPV types or by displaying L2 peptides on a more immunogenic carrier. There is also substantial research interest in the development of therapeutic vaccines, which seek to elicit immune responses against established HPV infections and HPV-induced cancers.

Therapeutic vaccines

In addition to preventive vaccines, such as Gardasil and Cervarix, laboratory research and several human clinical trials are focused on the development of therapeutic HPV vaccines. In general, these vaccines focus on the main HPV oncogenes, E6 and E7. Since expression of E6 and E7 is required for promoting the growth of cervical cancer cells (and cells within warts), it is hoped that immune responses against the two oncogenes might eradicate established tumors.

There is a working therapeutic HPV vaccine. It has gone through three clinical trials. The vaccine is officially called the MEL-1 vaccine but also known as the MVA-E2 vaccine. In a study it has been suggested that an immunogenic peptide pool containing epitopes that can be effective against all the high-risk HPV strains circulating globally and 14 conserved immunogenic peptide fragments from four early proteins (E1, E2, E6 and E7) of 16 high-risk HPV types providing CD8+ responses.

Therapeutic DNA vaccine VGX-3100, which consists of plasmids pGX3001 and pGX3002, has been granted a waiver by the European Medicines Agency for pediatric treatment of squamous intraepithelial lesions of the cervix caused by HPV types 16 and 18. According to an article published 16 September 2015 in The Lancet, which reviewed the safety, efficacy, and immunogenicity of VGX-3100 in a double-blind, randomized controlled trial (phase 2b) targeting HPV-16 and HPV-18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3, it is the first therapeutic vaccine to show efficacy against CIN 2/3 associated with HPV-16 and HPV-18. In June 2017, VGX-3100 entered a phase III clinical trial called REVEAL-1 for the treatment of HPV-induced high-grade squamous intraepithelial lesions. The estimated completion time for collecting primary clinical endpoint data is August 2019.

As of October 2020, there are multiple therapeutic HPV vaccines in active development and in clinical trials, based on diverse vaccine platforms (protein-based, viral vector, bacterial vector, lipid encapsulated mRNA).

Awards

In 2009, as part of the Q150 celebrations, the cervical cancer vaccine was announced as one of the Q150 Icons of Queensland for its role in "innovation and invention".

In 2017, National Cancer Institute scientists Douglas R. Lowy and John T. Schiller received the Lasker-DeBakey Clinical Medical Research Award for their contributions leading to the development of HPV vaccines.

Further reading

• World Health Organization (2011). The immunological basis for immunization series: module 19: human papillomavirus infection. World Health Organization (WHO). hdl:10665/44604. ISBN 9789241501590.
• World Health Organization (2016). Scaling-up HPV vaccine introduction. World Health Organization (WHO). hdl:10665/251909. ISBN 9789241511544.
• Phillips A, Hickie M, Totterdell J, Brotherton J, Dey A, Hill R, et al. (August 2020). "Adverse events following HPV vaccination: 11 years of surveillance in Australia". Vaccine. 38 (38): 6038–6046. doi:10.1016/j.vaccine.2020.06.039. PMID 32709432.
• Ramsay M, ed. (2019). "Chapter 18a: Human papillomavirus (HPV)". Immunisation against infectious disease. Public Health England.
• Hall E, Wodi AP, Hamborsky J, Morelli V, Schillie S, eds. (2021). "Chapter 11: Human Papillomavirus". Epidemiology and Prevention of Vaccine-Preventable Diseases (14th ed.). Washington D.C.: U.S. Centers for Disease Control and Prevention (CDC).

External links

• "HPV (Human Papillomavirus) Vaccine Information Statement". Centers for Disease Control and Prevention (CDC). August 2021.
• "Human Papillomavirus (HPV) Vaccines". National Institutes of Health (NIH). 18 June 2021.
• Papillomavirus Vaccines at the U.S. National Library of Medicine Medical Subject Headings (MeSH)