Two shots may be better than three

From Erin Scherer and the Galloway lab, Human Biology Division

To date, the human papillomavirus (HPV) vaccines are one of the most effective subunit vaccines developed, and come in bivalent, quadrivalent and nonavalent forms, which target two, four or nine HPV strains, respectively. These all produce long-lasting antibody responses against the major capsid protein L1, and are thus assumed to induce long-lived plasma B cells. In a previous study about a decade ago, young women who received the quadrivalent HPV (4HPV) vaccine and had already developed a primary immune response, showed a rapid antibody response following a booster dose given at 60 months post-vaccination. Since then, Drs. Scherer and Galloway and their colleagues developed methods to identify memory B cells imparted by the 4HPV vaccine, and designed this study to further evaluate B cell memory responses to 4HPV vaccination.

Existing guidelines for administration of the human papillomavirus (HPV) vaccine recommends a two-dose vaccine for adolescents, and a three-dose vaccine for young adults aged 18-26 years and immunocompromised individuals. To evaluate the quality of B cell memory generated from the 4HPV vaccine, Drs. Scherer and Galloway in the Human Biology Division designed a study to directly measure the secondary responses induced by B cell memory in sexually naïve young women following the third dose of the 4HPV vaccine, and also after a single booster 4HPV vaccine dose at month 24 following the three-dose vaccine series.  In their article published in the Journal of Infectious Diseases, they made the surprising finding that the B cell memory responses and antibody response rates were lower after the third vaccine dose compared to after the booster dose. Interestingly, there was an inverse correlation of the antigen-specific serum antibody levels at vaccination with B cell memory responses.

Additional vaccine doses and boosters serve to stimulate B cell memory to rapidly increase antibody levels. Although the third dose of vaccine has the potential to improve the quality of B cell memory by enhancing antigen affinity, the authors found that this was not the case by showing that there was no further affinity maturation in the vaccine specific B cell memory derived monoclonal antibodies. Antibodies examined after the booster at months 24 and 25 also did not show significant enhancement of somatic hypermutation, neutralization potency or affinity maturation. Since these findings show that secondary vaccine responses are reduced in the presence of vaccine-specific antibodies induced by the prior 4HPV doses, the authors suggest that the third HPV vaccine dose could be redundant, and that the timing of multi-dose vaccines schedules could be better determined by analyzing B cell memory response rates.

Although this was a pilot study that enrolled a small number of subjects, the implications of these findings on young people and other parties involved are significant. “We hope this work will stimulate discussions about reducing the HPV vaccination doses for all individuals, not just adolescents less than age 15.  More broadly, we think that vaccine manufacturers should establish vaccination schedules based on whether additional doses stimulate memory responses” said Dr. Galloway.

As for the likelihood and feasibility of a personalized vaccination schedule? Dr. Scherer said “Given the level of sophistication clinical trials are reaching with immunotherapy agents, I think it is highly feasible to analyze memory B cell and/or plasmablast responses in vaccine trials in order to optimize dosing and believe it should be done. However, I don’t think it is feasible to examine these responses on a person-to-person basis post-licensure, nor do I believe the field is ready to license personalized vaccines/vaccination schedules.” 

The initial dose of vaccine stimulates a memory B cell response. By the third dose there are such high levels of antibody that it neutralizes the third dose preventing boosting of memory B cell responses Figure provided by Dr. Galloway

Scherer EM, Smith RA, Carter JJ, Wipf GC, Gallego DF, Stern M, Wald A and Galloway DA. 2017. Analysis of memory B cell responses reveals suboptimal dosing schedule of a licensed vaccine. Journal of Infectious Diseases. doi: 10.1093/infdis/jix566.

Funding was provided by the National Institutes of Health and the Walker Immunotherapy Fellowship.

Research reported in the publication is a collaboration between Cancer Consortium members Denise Galloway (Fred Hutch) and Anna Wald (UW).