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 main article: vaccination policy 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