"The Lancet Oncology": HPV vaccine, one shot may do!

A while ago, a relative of a friend of Singularity Cake passed away from cervical cancer, and it has been only a few months since the last time I heard the diagnosis
.

The singularity cake can’t help but feel that when the aunt was young, it would be great if the human papillomavirus (HPV) vaccine was an anti-cancer artifact
.

In order to reduce the occurrence of similar tragedies, Singularity Cake appeals to all eligible friends to get HPV vaccine as soon as possible! There are currently bivalent, quadrivalent and ninth-valent HPV vaccines on the market.
The higher the valence, the more HPV genotypes targeted and the more comprehensive the protection
.

These vaccines are routinely given three shots, and their protective efficacy against cervical cancer is as high as 70%-90%
.

However, there are a large number of women who cannot afford such effective protection because they cannot afford the cost of vaccination
.

According to WHO estimates, the global HPV vaccine coverage rate in 2019 is only 15% [1]
.

The contradiction between vaccine supply and demand in low- and middle-income countries is particularly prominent, and about two-thirds of the countries cannot include HPV vaccine in their national immunization plans [2]
.

It is gratifying that recently, the Lancet Oncology published a study that is expected to alleviate the supply crisis of HPV vaccine
.

The research team led by Professor Partha Basu of the International Agency for Research on Cancer pointed out that in the past 10 years after vaccination, the single-dose quadrivalent HPV vaccine has the same protective effect against high-risk HPV16 and HPV18 (nearly 70% of cervical cancers caused by) persistent infections.
Or the three doses of tetravalent vaccine are equivalent, and the potency is 95.
4%, 93.
1% and 93.
3% respectively [3]
.

In other words, women who cannot afford the cost of three or two shots of HPV vaccines are the second best, and only one shot of quadrivalent vaccine may also be well protected
.

A screenshot of the first page of a paper is usually very few people will only get one shot when they should have three shots
.

The reason why this research can be carried out is to start with a notice to stop vaccination
.

On September 1, 2009, researchers began recruiting unmarried women aged 10-18 years in 9 regions of India to participate in a randomized cluster of two-dose and three-dose quadrivalent HPV vaccine (manufactured by Merck & Co.
) Controlled test
.

The study originally planned to recruit 20,000 women, but when the recruitment and vaccination came to an end, another HPV vaccine trial reported 7 deaths not related to the vaccine [4]
.

For security reasons, the Indian government halted all related research
.

At this time, some subjects received only one shot, and some subjects were supposed to have received three shots but only received two shots
.

After the suspension of vaccination, this clinical trial was automatically transformed into a longitudinal cohort study and re-divided into 4 groups according to the actual vaccination situation: three-injection group (4348 people; day 0, 60 days, 180+ days vaccination), the original two-injection group (4980 people; vaccination on day 0, 180+ days), three-to-two injection group (3452 people; day 0, vaccination on 60+ days) and one-shot group (4949 people)
.

In order to study the protective efficacy of the vaccine, the researchers also recruited two batches of age and residence matching the above-mentioned subjects in 2013-2015 (1541 people) and 2017-2019 (3631 people), but who had not received the HPV vaccine.
Married women served as controls
.

The research flow chart tracks the HPV vaccine re-vaccinations and illnesses of the research subjects every year, and the follow-up will continue until August 2026
.

In addition, the first cervical specimen was collected 18 months after marriage or 6 months after the first childbirth (whichever is the earlier), and one specimen was collected every year for 3 years.
Luminex was used to detect 21 HPV genotypes (high risk).
Type HPV16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68a, 68b, 70, 73, 82; low-risk HPV6 and HPV11), Assess HPV infection
.

Among them, the subjects newly infected with HPV in the fourth year need to be re-examined in the next year
.

Married subjects over 25 years of age were screened for cervical cancer using HC2 technology
.

Those who were screened positive were further used digene PS test to determine the infection type (HPV16, 18, 45), and at the same time underwent colposcopy.
If the score was ≥5, a biopsy was done, and if the score was less than 5, HC2 was reviewed in the next year
.

The control population from 2013 to 2015 was tested for both HPV infection and cervical cancer screening, and the control population from 2017 to 2019 was only screened for cervical cancer
.

In order to ensure the objectivity of the results, all medical staff involved in testing and inspections do not know the vaccination status of the study subjects
.

The primary end point of the study is the persistent infection of HPV16, HPV18 or both (hereinafter abbreviated as HPV16/18) (two consecutive tests are positive and the interval between the two tests is at least 10 months), the secondary end point is HPV16/18 Cervical intraepithelial neoplasia (CIN2+) related to HPV16/18 with a single infection
.

Other exploratory outcome indicators include single or persistent infections of HPV6/HPV11, HPV31/HPV33/HPV45 or other genotypes
.

According to the infection situation, the protective effect of HPV vaccine can be calculated (1-HPV infection rate of vaccinated persons/HPV infection rate of non-vaccinated persons)
.

In total, a total of 17,729 women were vaccinated with HPV vaccine, and 61.
6% of them were tested for HPV genotype
.

After an average follow-up of 9.
0 years, the single HPV16/18 infection rate of vaccinated patients was 3.
1% (95% CI: 2.
8%-3.
5%), which was significantly lower than that of non-vaccinated patients (9.
4% [95% CI: 7.
9%-11.
0% ])
.

The single infection rate (3.
2%) of the one-injection group was similar to that of the three-injection group (3.
0%) and the two-injection group (2.
7% and 3.
6%)
.

About 72.
7% (6673) of the study subjects in each vaccinated group compared with the non-vaccinated group HPV infection provided at least 2 infection evaluation results, which can determine the continuous HPV infection
.

The HPV16/18 persistent infection rate of vaccinated patients was 0.
1% (95% CI: 0.
0%-0.
2%), which was significantly lower than that of non-vaccinated patients (2.
5% [95% CI: 1.
7%-3.
6%])
.

The persistent infection rate (0.
0%) in the one-injection group was similar to that in the three-injection group (0.
1%) and the two-injection group (0.
1% and 0.
2%)
.

Although the tetravalent vaccine does not cover HPV31, 33 and 45, it has a certain cross-protection effect on these three genotypes
.

The results of the study showed that the single infection rate of these three genotypes among vaccinated persons (4.
0%) was lower than that of non-vaccinated persons (10.
0%).
There was no significant difference in the single infection rate of different injection groups, and the result of persistent infection was also the same
.

For tetravalent vaccine targeting genotypes (HPV6, 11, 16, 18) and cross-protection genotypes (HPV31, 33, 45), the rules are the same
.

In addition to the infection rate, the researchers also compared the protective efficacy of the vaccines in each group.
The results found that the efficacy of preventing a single HPV16/18 infection was 63.
5% when only one shot, compared with two shots (67.
7%) and three shots (66.
4%).
) There is no significant difference in effectiveness
.

There was no significant difference in the protective efficacy of each injection group against cross-protection genotypes and single infection of 21 genotypes
.

Protective effects of vaccination on HPV16/18 (A) and HPV 31, 33, 45 (B).
The efficacy of one shot, two shots, and three shots to prevent persistent HPV16/18 infection is 95.
4%, 93.
1% and 93.
3%, respectively.
The efficacy of persistent infection of 21 genotypes was 35.
4%, 36.
7%, and 39.
3%, respectively
.

The proportion of vaccinated and non-vaccinated patients with positive cervical cancer screening was 4.
1% and 6.
0%, respectively
.

In the study, only one case of CIN3 patient was found in the subject who received a single injection, and her Luminex and digene PS test results were negative
.

No CIN2 or invasive cancer was found in the vaccinated persons, and 5 cases of CIN2 or CIN3 were found in the non-vaccinated persons, of which 3 cases were related to HPV16/18 infection, and 1 case of invasive cancer was not related to HPV16/18 infection
.

Comparison of HPV infection protection efficacy between the vaccinated group and the non-vaccinated group In addition to the protection efficacy of the vaccine, another issue that everyone is more concerned about is the durability of the protection provided by the vaccine
.

Although the study has no relevant data, another study showed that the antibody concentration of single-dose vaccinators stabilized within 18-24 months after vaccination, and remained higher than the antibody level after natural infection for at least 10 years [ 5,6]
.

In some countries that have included HPV vaccines in their immunization programs, single-dose vaccines have shown comparable efficacy to multi-dose vaccines in preventing HPV infection, anogenital warts, and CIN2+ lesions, which is consistent with the conclusions of this study [7-11]
.

Of course, the study inevitably has some limitations.
For example, after losing the characteristics of randomization in clinical trials, the groups may not be completely comparable; for non-tetravalent vaccines targeting non-cross-protected genotypes, ideally, the vaccinated group and the non-cross-protected genotype The infection rate of the vaccinated group should be almost right, and now the former is lower than the latter, suggesting that the choice of the non-vaccinated group may not be so perfect, and it does not exactly match the vaccinated group
.

In low- and middle-income countries, there are still many women who cannot afford the HPV vaccine.
Coupled with the tilt of medical resources caused by the new crown, the problem of HPV vaccine coverage is even worse [12]
.

The results of a preprint model study showed that even if a single dose of HPV vaccine is slightly less effective, as long as the coverage rate is high, it can produce higher health benefits at the population level than two doses of vaccine [13]
.

The herd immunity generated through high coverage may make up for the lack of protection of a single-dose vaccine at the individual level over time [14]
.

Therefore, reasonable introduction of a single-dose HPV vaccine and increased vaccine coverage may be expected to reduce the occurrence of cervical cancer in a more economical manner
.

References[1] WHO.
Immunization coverage.
July 15, 2021.
https:// WHO.
Immunization, vaccines and biologicals.
https :// Basu P, Malvi SG, Joshi S, et al.
Vaccine efficacy against persistent human papillomavirus (HPV) 16/18 infection at 10 years after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a multicentre, prospective, cohort study [published online ahead of print, 2021 Oct 8].
Lancet Oncol.
2021;S1470-2045(21)00453-8.
doi:10.
1016/S1470-2045(21)00453-8[4] Sankaranarayanan R, Basu P, Kaur P, et al.
Current status of human papillomavirus vaccination in India's cervical cancer prevention efforts.
Lancet Oncol.
2019;20(11):e637-e644.
doi:10.
1016/S1470-2045(19)30531-5[5] Basu P, Muwonge R, Bhatla N, et al.
Two-dose recommendation for Human Papillomavirus vaccine can be extended up to 18 years-updated evidence from Indian follow-up cohort study.
Papillomavirus Res.
2019;7:75-81.
doi:10.
1016/j.
pvr.
2019.
01.
004[6] Kreimer AR, Sampson JN, Porras C, et al.
Evaluation of Durability of a Single Dose of the Bivalent HPV Vaccine: The CVT Trial.
J Natl Cancer Inst.
2020;112(10):1038-1046.
doi:10.
1093/jnci/djaa011[7] Rodriguez AM, Zeybek B, Vaughn M, et al.
Comparison of the long-term impact and clinical outcomes of fewer doses and standard doses of human papillomavirus vaccine in the United States: A database study.
Cancer.
2020;126(8):1656-1667.
doi:10.
1002 /cncr.
32700[8] Brotherton JM, Budd A, Rompotis C, et al.
Is one dose of human papillomavirus vaccine as effective as three?: A national cohort analysis.
Papillomavirus Res.
2019;8:100177.
doi:10.
1016/j.
pvr.
2019.
100177[9] Verdoodt F, Dehlendorff C, Kjaer SK.
Dose- related Effectiveness of Quadrivalent Human Papillomavirus Vaccine Against Cervical Intraepithelial Neoplasia: A Danish Nationwide Cohort Study.
Clin Infect Dis.
2020;70(4):608-614.
doi:10.
1093/cid/ciz239[10] Markowitz LE, Naleway AL, Klein NP, et al.
Human Papillomavirus Vaccine Effectiveness Against HPV Infection: Evaluation of One, Two, and Three Doses.
J Infect Dis.
2020;221(6):910-918.
doi:10.
1093/infdis/jiz555[11] Zeybek B , Lin YL, Kuo YF, Rodriguez AM.
The Impact of Varying Numbers of Quadrivalent Human Papillomavirus Vaccine Doses on Anogenital Warts in the United States: A Database Study.
J Low Genit Tract Dis.
2018;22(3):189-194.
doi:10.
1097/LGT.
0000000000000401[12] Ginsburg O, Basu P, Kapambwe S, Canfell K.
Eliminating cervical cancer in the COVID-19 era.
Nat Can 2021; 2: 133–34.
[13] Prem K, Choi YH, Bénard E, et al.
Global impact and cost-effectiveness of one-dose versus two-dose human papillomavirus vaccination schedules: a comparative modelling analysis.
medRxiv 2021; published online Feb 8.
https://doi.
org/10.
1101/2021.
02.
08.
21251186 (preprint).
[14] International Agency for Research on Cancer/WHO.
Primary end-points for prophylactic HPV vaccine trials.
IARC Working Group report, vol 7.
Lyon: IARC, 2014.
Author of this articleBioTalkerGlobal impact and cost-effectiveness of one-dose versus two-dose human papillomavirus vaccination schedules: a comparative modelling analysis.
medRxiv 2021; published online Feb 8.
https://doi.
org/10.
1101/2021.
02.
08.
21251186 (preprint).
[ 14] International Agency for Research on Cancer/WHO.
Primary end-points for prophylactic HPV vaccine trials.
IARC Working Group report, vol 7.
Lyon: IARC, 2014.
Author of this articleBioTalkerGlobal impact and cost-effectiveness of one-dose versus two-dose human papillomavirus vaccination schedules: a comparative modelling analysis.
medRxiv 2021; published online Feb 8.
https://doi.
org/10.
1101/2021.
02.
08.
21251186 (preprint).
[ 14] International Agency for Research on Cancer/WHO.
Primary end-points for prophylactic HPV vaccine trials.
IARC Working Group report, vol 7.
Lyon: IARC, 2014.
The authorBioTalker