In most people's minds, as an important tool against viral invasion, vaccines need to be given multiple doses, including the first dose and the booster needle.
But a piece of advice from the World Health Organization (WHO) shatters that perception.
According to the Opinion of the World Health Organization's Strategic Group of Experts on Immunization (SAGE), only 1 dose of the human papillomavirus (HPV) vaccine can produce the same immune effect as 2-3 doses, which can effectively prevent cervical cancer caused by HPV infection.
A stone stirs up a thousand layers of waves. On April 14, the domestic HPV vaccine concept stock fell sharply, and related topics such as "HPV vaccine can only be given 1 injection with 3 injections" and "HPV vaccine only 1 injection has yet to be confirmed" quickly rushed to the hot search.
After giving 1 injection, do you still need the 2nd injection? Many netizens are confused under the topic...
"Judging from the mechanism of action of the vaccine and the vaccination procedure of the active vaccine, the cervical cancer vaccine, as a non-live vaccine and a recombinant protein vaccine, has an extraordinary procedure of only 1 dose." Vaccine expert Taurina told the health community.
Theoretically, most vaccines require at least 2 doses, the first dose is the primary immunization, the follow-up dose is to strengthen the immunity, and the antibodies produced by the strengthening of the immunization will generally be much higher than the initial immunization.
Live vaccines have a better immune effect due to simulated natural infection, and there are only 1 dose of vaccination, such as live hepatitis A vaccine, live spraying influenza vaccine, rubella vaccine, etc.; non-live vaccines are generally given 2-4 doses.
"But practice comes first, theory comes second." Taurina added that the World Health Organization's recommendation of a 1-dose procedure for cervical cancer vaccine this time, and the use of "solid protection" as a definitive statement, must be a deliberate result after having a large amount of practical evidence, "I am willing to support it."
"As a global health policymaker, the World Health Organization," issuing such a recommendation at this time, which is not urgent, must be based on the results of clinical research, and I think its conclusions are credible." Vaccine industry veteran Lin Yongzhao (pseudonym) also told the health community.
However, a number of HPV vaccine companies do not think so.
Global vaccine giant Merck said that there is a lot of uncertainty in the single dose HPV vaccine regimen, its long-term protection against certain HPV-related cancers and diseases is currently very limited, and there is no data to show its effectiveness against HPV-induced non-cervical cancer cancers and other groups such as men and immunocompromised people.
In addition, a spokesperson for Merck's headquarters noted that the draft high-level recommendations of the WHO Strategic Expert Group on Immunization are not final and await review by the Director-General of the World Health Organization. These reports are considered final when they are published in the Weekly Epidemiological Record.
From 1 April 2022, the UK has officially adjusted the HPV vaccination plan for people over 15 years old, from a total of 3 injections to 2 injections, with at least 6 months between the two doses.
"The evaluation criteria for HPV vaccines in China are more stringent than in foreign countries, and in fact, the standards for cancer prevention have been used, and the observation time is too long." Taurina told the health community.
He also said that with his "conservative" judgment of China's vaccine industry and supervision, the vaccination procedure on the Chinese cervical cancer vaccine instructions is unlikely to have a major adjustment in a few years; for global vaccine companies such as Merck, the possibility of changing the vaccination procedures within 2-3 years is relatively small; but for individuals, according to the new procedures recommended by the World Health Organization, 1-2 doses less than the vaccination procedures on the instructions are completely operational.
Under the controversy, can the 1-dose vaccination regimen land on the mainland?
1 dose instead of 3 doses, where does the conclusion come from?
In September 2009, the International Agency for Research on Cancer (IARC), part of the World Health Organization (WHO), launched a trial in India to compare the protective efficacy of 2 and 3 doses of tetravalent HPV vaccine (Jadasio).
The trial was originally planned to enroll 20,000 unmarried women aged 10-18 years, but near the end of the recruitment and vaccination, another HPV vaccine trial reported 7 unrelated deaths.
For safety reasons, the Indian government halted the test.
At this point, some of the subjects were given only 1 injection, and some subjects were supposed to have given 3 injections, but only 2 injections.
After the suspension of vaccination, this clinical trial was automatically converted into a longitudinal cohort study and re-divided into 4 groups according to the actual vaccination situation: 3-dose group (4348 people; day 0, 60 days, 180+ days vaccination), the original two-needle group (4980 people; day 0, 180+ days vaccination), 3-to-2 injection group (3452 people; day 0, day 60+ vaccination) and 1 injection group (4949 people).
Later, in 2013-2015 (1541 people) and 2017-2019 (3631 people), the researchers recruited two groups of married women who matched the age and place of residence of the above study subjects, but did not receive HPV vaccine as controls.
Research flowcharts
The researchers followed subjects annually on HPV vaccination and illness, and follow-up will continue until August 2026. At present, the trial has obtained 10 years of efficacy and immunogenicity data.
These clinical data are one of the important evidences proposed by the World Health Organization to modify the immunization program for HPV vaccines. The researchers believe that the 10th year data show that 3 HPV vaccination programs (single dose, two doses (0 and 6 months), 3 doses) all provide a similar anti-HPV-16/18 efficacy of more than 90%, and the protective efficacy lasts for at least 10 years after vaccination.
HPV infection was compared between the vaccinated and unvaccinated groups
Protective effect of vaccination against HPV16/18(A) and HPV31, 33, 45(B).
In addition, the World Health Organization reviewed evidence from three trials conducted in Kenya, Tanzania and Costa Rica.
In the KEN-SHE trial in Kenya, 2250 female subjects aged 15-20 years were randomized into three groups: bivalent (Cyrus), nine valent (Jadash 9), and delayed vaccination (meningococcal vaccine). The results showed that the single dose of the Cyrus and Jadasius 9 vaccines was very effective; the efficacy of the two vaccines against persistent HPV-16/18 infection at the 18th month was 97.5%.
At the same time, the researchers combined data from a single dose vaccine with two published publications (Joura et al. NEJM. 2015）、（Harper et al. Lancet. 2014) data were compared and concluded that single-dose efficacy estimates were similar to those reported in multi-dose regimens.
The results of the DoRIS trial in Tanzania showed that 24 months after receiving the Cyrus and Jadashio 9 vaccines, a single dose of immunogenicity was no less than the multi-dose procedure.
The results of the Costa Rican HPV vaccine (CVT) trial showed that after single-dose administration of Cyrene, the levels of HPV-16 and HPV-18 antibodies in all subjects persisted several times that of natural infection for up to 11 years; in addition, the efficacy of the single-dose bivalent Cyrene regimen was similar to that of the multi-dose regimen after the administration of the Cyrene monotherapy, although the number of subjects was small.
In summary, the World Health Organization believes that the above experimental evidence shows that hpv-16/18 antibodies can also be detected in women with only one dose of HPV vaccine, and the protective efficiency against HPV-16/18 infection is similar compared with multiple doses.
The World Health Organization therefore recommends modifying the immunization program to:
Women aged 9-14 years (the highest priority) are given 1 or 2 doses;
1 dose or 2 doses for women aged 15-20 years;
Women over 21 years of age receive 2 doses (6 months apart).
For immunocompromised individuals, including people with HIV infection, 3 doses should be given, if feasible. If conditions do not permit, at least 2 doses are given. The World Health Organization stresses that there is limited evidence on the efficacy of single doses in this population.
Clinical endpoint controversy, persistent infection vs precancerous lesions?
Although the World Health Organization's recommendation for a single dose of HPV vaccination is based on a review of trial data, not only the relevant vaccine companies have expressed doubts, but also a number of brokers.
Guosen Securities Pharmaceutical Team pointed out in the research report that most of the research results reviewed by the WHO Immunization Strategic Expert Group take persistent infection/immunogenicity in the small age group as the alternative endpoint, and the standard is advanced, which may lead to a decrease in the accuracy of the estimation of the final efficiency, while the peak of single dose vaccination and long-term antibody titers are lower than 2/3 doses of immunization procedures, and the long-term protective efficacy of cervical cancer still needs more data and longer dimensions of continuous tracking.
Pacific Securities also believes that through the comparison of data on persistent infection, the protective effect of the single needle method relative to the negative control group can be explained, but the proportion of infected people through different vaccination procedures is not fully explained.
The advance of clinical trial endpoints is one of the main reasons why the industry has questioned the WHO's conclusions.
Theoretically, 80% of sexually active women have HPV infection, about 90% of which can rely on their own immune system to naturally resolve within 1-2 years, a small number become persistent infections, and eventually about 1% of patients develop cervical cancer.
Usually, only high-risk HPV infection that lasts for many years causes cytological abnormalities, and it takes about 5-10 years from HPV infection to cervical cancer.
The premarket clinical studies of hpv vaccines currently on the market have used high-grade cervical intraepithelial neoplasia (CIN) as the main clinical endpoint.
But the World Health Organization has frequently proposed in recent years that the standard could be brought forward:
In 2014, it recommended that persistent hpv infection in the cervix or anus for 6 months or more be used as an alternative endpoint indicator for clinical trials to assess vaccine effectiveness.
In 2016, it recommended changing the criteria for evaluating effectiveness to persistent infection.
At present, countries such as the European Union and Japan have accepted the results of the study of persistent HPV infection as the evaluation endpoint.
In February 2022, the UK Joint Commission on Vaccination and Immunization (JCVI) published the Interim Recommendations for Single Dose HPV Vaccination. The report notes that there is now sufficient clinical evidence to recommend that the vaccination schedule for adolescents under 14 years of age be changed from 2 doses of HPV vaccine to a single dose.
In fact, the above-mentioned UK commission has been aware of the potential of single dose HPV vaccine since 2018, while the review of the single dose vaccination plan was carried out in June 2020. "Although the evidence (at the time) suggests that single-dose HPV vaccination programmes are the way forward, we hope to see more evidence, particularly on the nine-valent vaccine, before making recommendations on HPV vaccination programmes." The report reads.
Now, after reviewing the clinical evidence from the Kenyan KEN-SHE trial, the DoRIS trial in Tanzania, the International Agency for Research on Cancer in India, the CVT trial in Costa Rica, and several studies on the effectiveness of the nine-valent vaccine, the ABOVE-mentioned UK Committee has found the evidence to move to a single dose convincing and similar to or even higher than the evidence supporting a change from 3 doses to 2 doses.
"After HPV vaccination, most of the decline in antibodies occurs in the first 6-8 months after vaccination, followed by a stabilization phase, and it has been observed that the antibodies remain stable for more than 10 years. The effectiveness of a single dose of HPV vaccine is as high as the effectiveness of the observed 2 or 3 doses of vaccine." The above-mentioned British commission said.
As of now, the UK Health Safety Agency (UKHSA) has not passed the temporary recommendation, but since 1 April 2022, the UK has officially adjusted the HPV vaccination plan for people over 15 years old, from the original 3 doses to 2 injections, with at least 6 months between the two doses.
"In terms of the development of cervical cancer, persistent infection is the first step, cancer is the second step, if clinical trials show that the protective efficacy of a single dose of vaccine against persistent infection is already relatively high, then I think the Conclusion of the World Health Organization is not a problem." Lin Yongzhao told the health community.
Taurina agrees that the HPV vaccine is sufficient as long as it prevents persistent infection.
"The evaluation criteria for HPV vaccines in China are more stringent than in foreign countries, and in fact, the standards for cancer prevention have been used, and the observation time is too long."
In May 2020, Qiao Youlin, a member of the Expert Group on Cancer Prevention and Control of the Director-General of the World Health Organization, published a paper in the China Science Foundation as a corresponding author, pointing out that a large number of data proved the scientific and rationality of continuous HPV infection (two consecutive positive tests for the same HPV subtype at intervals of at least 6 months) as the endpoint for evaluating the effectiveness of HPV vaccines. Under the condition of ensuring high-quality clinical research and evaluation, in order to accelerate the research and development of HPV preventive vaccines in mainland China, relevant departments should actively consider the feasibility of continuous HPV infection as an alternative endpoint observation index for clinical evaluation on the basis of the current scientific evidence.
Who's whose recommendations are difficult to land?
In addition to the controversy over the endpoints of clinical trials, the industry believes that another reason why the WHO's recommendations are difficult to land in China is that the World Health Organization proposed to replace the current 2/3 vaccination procedure with 1/2 injection, mainly to improve the HPV vaccine coverage in low- and middle-income countries, but the possibility of the single needle method being accepted by the State Food and Drug Administration of China is low.
"Historically, the World Health Organization has recommended replacing CIN2 with persistent infection data as a clinical endpoint after listing two HPV vaccines on GlaxoSmithKline and Merck. The purpose of the recommendations is that the time to clinical trials of hpv virus vaccines can be reduced. However, for the sake of safety and protection, the mainland drug regulatory authority insists on CIN2 as the clinical endpoint, so as to effectively ensure the protective effect of the vaccine. From this point of view, the single stitch method is less likely to be accepted." Pacific Securities said in the research report.
But in fact, on the one hand, as mentioned earlier, the evidence for replacing CIN2 with persistent infection as a clinical endpoint has become more and more abundant in recent years; on the other hand, the mainland faces the same challenge as the World Health Organization – increasing the penetration of HPV vaccines.
In November 2020, the World Health Organization released the Global Strategy to Accelerate the Elimination of Cervical Cancer, in which 194 countries, including China, pledged to vaccinate more than 90% of girls aged 9-14 years against HPV by 2030.
In 2017, the bivalent HPV vaccine was approved for the first time in the mainland, and then the quadrivalent and nine-valent vaccines have also entered the Chinese market. According to the Cinda Securities Research Report, from 2017 to 2021, the total number of HPV vaccine batches issued in mainland China is about 146, 713, 1087, 1544 and 32.49 million respectively; according to the OECD database, the female population aged 9-45 in mainland China will be about 322 million in 2021, and according to the rough calculation of the 3-dose vaccination procedure, the cumulative penetration rate of HPV vaccine in mainland China in 2021 will be 6.99%.
The mainland is still far from the promised 2030 vaccination target. The main reason behind the slow increase in the penetration rate of HPV vaccines in the mainland is the lack of vaccine production capacity.
Sullivan data predicts that by 2025, there will still be 234 million women aged 9 to 45 in the country who will not be vaccinated against HPV, and an additional 702 million doses may be needed in addition to the existing capacity assuming 3 doses per person.
"Single-dose vaccination can help achieve the 2020 Cervical Cancer Eradication Initiative more quickly." Simelela, WHO Assistant Director-General, said a single dose of vaccination is less costly, takes up fewer resources and is easier to manage, with savings in health money and human resources available for other health matters.
A study of HPV vaccination intentions in the Beijing area (Li Juan et al., 2021) showed that the top 3 donor factors hindering HPV vaccination were:
Insufficient staff
The workload increases
Vaccines are in short supply
Among the hpv-resistant age vaccinated populations, the main reasons for not being vaccinated are:
There is no time for vaccination
Vaccine prices are high
Concerns about vaccine safety and efficacy
In addition, in another survey that expanded the scope to the whole country (Zhang Xi et al., 2021), 36.86% of the women surveyed were willing to pay ≧ 1000 yuan / 3 doses to buy HPV vaccines, and 45.15% of women were only willing to pay ≦ 100 yuan / 3 doses, and the price factor seriously hindered the vaccination of HPV vaccines.
At present, the hpvic vaccines that have been listed worldwide are divided into 3 categories: bivalent, quadrivalent, and nine-valent, involving 5 products from 4 manufacturers, namely GlaxoSmithKline's bivalent HPV vaccine, Merck's quadrivalent HPV vaccine, Merck's nine-valent HPV vaccine, Wantai Bio's divalent HPV vaccine, and Watson Bio's bivalent HPV vaccine.
Among them, the latter two are domestic vaccines, which are only sold in China; Merck's HPV vaccine is sold exclusively by Zhifei Biologics in China.
From the pricing point of view, the cheapest domestic divalent HPV vaccine, the price of a single dose is about 300 yuan, the immunization program is 3 doses, and women aged 9-14 years can also use 2 doses of the program. But even that price is beyond what most women in the survey are willing to pay.
In order to improve the penetration rate of HPV vaccine in the mainland, the National Health Commission will gradually implement free or subsidized vaccination of bivalent HPV vaccine for age-appropriate people in 15 pilot areas from 2021, and encourage qualified areas to actively adopt multiple financing models to gradually carry out free HPV vaccination.
"If WHO updates the cervical cancer vaccine position paper, it is not excluded that regions that will subsequently introduce free vaccination policies will adopt this one-dose strategy that is not in the manual but halves the cost, because the government pays for the free vaccine and is very cost-sensitive." Taurina said.
However, Tao Lina also said that with its "conservative" judgment of China's vaccine industry and supervision, the vaccination procedure on the Chinese cervical cancer vaccine specification is unlikely to have a major adjustment in a few years; for global vaccine companies such as Merck, the possibility of changing the vaccination procedure within 2-3 years is relatively small; but for individuals, according to the new procedure recommended by the World Health Organization, it is completely feasible to receive cervical cancer vaccine by 1-2 doses less than the vaccination procedure on the instructions.
"The vaccination procedure is determined based on the results of previous clinical trials, and if it is to be changed, it is necessary for the company to submit a new clinical trial plan to the State Drug Administration, and the clinical trial can be carried out after approval, and if the expected results are obtained, the original vaccination procedure can be changed." Lin Yongzhao said that from past experience, in the short term, it is less likely that the national level or enterprise level will take the initiative to promote the adjustment of vaccine immunization procedures.
Du Heng, Senior Program Officer of the Bill & Melinda Gates Foundation, told the health community: "We call on domestic HPV vaccine R&D manufacturers and clinical researchers to strengthen the clinical development and real-world research of single-dose procedures to make domestic HPV vaccines more in line with the who-recommended immunization procedures."
Resources:
【1】 WHO Strategic Expert Group on Immunization April 2022 Meeting Highlights. World Health Organization.
[2] The British Committee Interim Advice on A One-dose Schedule for the Routine HPV Immunisation Programme. The British Commission
【3】 HPV Immunisation Programme: Changes from April 2022 Letter. UKHSA
[4] Xie Yu,Chen Limei. Hot topic丨 HPV vaccination is enough? The World Health Organization gives new recommendations.
[5] Si Keyi. "Lancet Oncology": HPV vaccine, a shot may be enough! Scientific studies have found that one dose of tetravalent HPV vaccine is comparable to two and three doses of high-risk HPV infection within 10 years. Singularity Net
[6] Zhao Yuqian,Zhang Shaokai,Qiao Youlin. Strategic considerations on the evaluation of the effectiveness of HPV preventive vaccine clinical trials. Science Foundation of China. 2020. 05.
[7] LI Juan,LI Xiaomei,ZHANG Zhujiazi,ZHAO Dan,PAN Jingbin,LU Li,WU Jiang. HPV vaccine recommendation and population vaccination behavior analysis of vaccination clinics in Beijing. Public Health in China. 2021.12.
[8] Zhang Xi,Su Zheng,Xu Huifang,Yu Yanqin,Li Yang,Qiao Youlin. A summary analysis of HPV vaccine cognition and willingness to vaccinate in women in Chinese mainland, 2009-2016. Chinese Public Health. 2021.12.
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Written by | Shen Mengxia
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