Fewer HPV vaccine doses may be safe, effective

Two doses of quadrivalent HPV vaccine administered at least 6 months apart appeared to protect against incident and persistent HPV 16, 18, 6 and 11 as well as a three-dose schedule, according to results of a prospective cohort study conducted by the Indian HPV Vaccine Study Group.

These results support the WHO recommendation of administering two doses, according to researchers.

Further, the short-term protection conferred by one dose of HPV vaccine against persistent HPV 16, 18, 6 and 11 infections appeared similar to that achieved by two or three doses, warranting further study, results showed.

A worldwide increase in HPV vaccination could occur if researchers confirmed that fewer than three doses produced the same efficacy as three doses, according to study background.

Thus, Rengaswamy Sankaranarayanan, MBBS, MD, special advisor and group head of the screening group at International Agency for Research on Cancer in Lyon, France, and colleagues sought to compare the immunogenicity and frequency of persistent infection and cervical precancerous lesions caused by vaccine-targeted HPV following vaccination.

Sankaranarayanan and colleagues originally planned to conduct a cluster-randomized trial comparing two vaccine doses — given on days 1 and 180 or later — with three doses, given on days 1, 60 and 180 or later.

However, because the researchers had to suspend recruitment and vaccination due to unrelated events — which left some enrolled girls unable to be vaccinated or to receive their full schedule of vaccinations — they decided to reanalyze their data as an observational cohort study.

The study included data from unmarried girls aged between 10 years and 18 years. The researchers divided the girls into four cohorts: those who received three vaccine doses, on days 1, 60 and 180 or later; those who received two doses, on days 1 and 180 or later; those who received two doses, on days 1 and 60 by default; and those who received one dose by default.

Key study outcomes included immunogenicity in terms of L1 genotype-specific binding antibody titers, neutralization of antibody titers, antibody avidity after vaccination for vaccine-targeted HPV types, and incident and persistent HPV infections.

Prior to suspension, the researchers recruited 17,729 girls from a total of 21,258 eligible girls (83%).

Overall, 4,348 girls (25%) received three vaccine doses; 4,979 girls (28%) received two doses on days 1 and 180 or later; 3,452 girls (19%) received two doses on days 1 and 60; and 4,950 girls (28%) received a single dose.

Median follow-up was 4.7 years (interquartile range, 4.2-5.1).

Immune response among girls who received two doses appeared noninferior to those who received three doses at 7 months (median fluorescence intensity ratio for HPV 16 = 1.12; 95% CI, 1.02-1.23; for HPV 18 = 1.04; 95% CI, 0.92-1.19).

However, the two-dose approach appeared inferior at 18 months (HPV 16 = 0.33; 95% CI, 0.29-0.38; HPV 18 = 0.12; 95% CI, 0.1-0.14).

The geometric mean avidity indices after fewer than three doses by design and default appeared noninferior to those after three doses; further, fewer than three doses by design and default induced detectable concentrations of neutralizing antibodies to all four vaccine-targeted HPV types. However, the concentration was much lower after one dose, according to the researchers.

The researchers had access to cervical samples from 2,649 participants. Testing showed that the frequency of incident HPV 16, 18, 6 and 11 infections remained similar across vaccination dose.

Further, the testing of at least two samples from 838 participants showed no persistent HPV 16 or 18 infections in any study group by the end of follow-up.

In addition to the loss of randomization due to suspension of enrollment, the researchers acknowledged the absence of memory B-cell response data and the potential for biases introduced by the halt in enrollment as potential limitations.

“A single dose of HPV vaccine, providing strong and sustained protection against HPV infection in the long term, is the best way to overcome the barriers to vaccine uptake globally,” Sankaranarayanan and colleagues wrote. “Our findings support the WHO recommendation to use two doses separated by 6 months or more for vaccination of young girls, and indicate that a single dose of the HPV vaccine merits further assessment.”

In an accompanying editorial, Julia M.L. Brotherton, MD, MPH, of the Victorian Cytology Service in East Melbourne, Australia, discussed the different effects the one-dose vaccination schedule has demonstrated in real-world studies.

“What is fascinating about the data for the effect of one dose of quadrivalent HPV vaccine in real-world programs is the evidence of a reduction in clinical disease but not the same degree as that reported for two or three doses,” Brotherton wrote. “For genital warts, any number of doses provides better protection than none, but three doses are superior to two, which are superior to one. Similarly, Australian data suggest that for cervical abnormalities, fewer than three doses of vaccine provide significant but reduced absolute protections. Perhaps further analysis correlating antibody titer, or other markers of immunity, with clinical efficacy in such studies will establish why there are differences between the findings of Sankaranarayanan and colleagues’ study of equal efficacy and post-vaccination observational studies that suggest a dose-dependent effect.” – by Cameron Kelsall

Disclosure: The Bill & Melinda Gates Foundation provided funding for this study. Sankaranarayanan reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures. Brotherton reports grant support from BioCSL/Merck.