<![CDATA[Can we use one dose of HPV vaccine to ensure long term protection?]]>

Why is HPV vaccination important?
Cervical cancer affects more than half a million women annually, with 88% of mortality occurring in low-income nations, where cervical cancer is a leading cause of cancer death among women. Sadly, if current trends go unabated, the number of cases is expected to increase due to population growth alone. Yet, we have the tools to interrupt this devastating trajectory.

In May 2017, the 70th World Health Assembly endorsed an updated list of evidence-based interventions for some of the deadliest diseases, including cancer. Of 88 proposed interventions, 16 were considered the most cost-effective and feasible for implementation-- vaccinating girls aged 9-13 years against HPV and screening women aged 30-49 years for cervical cancer made this important list.

It is our greatest hope that governments can facilitate the implementation of these life-saving measures. But, HPV vaccine uptake and cervical cancer screening implementation has been poor in many world regions. The first issue of HPV WORLD focused on bringing cervical cancer screening via HPV detection methods to emerging economies. This present issue focuses on HPV vaccination, and presents the state-of-the-science around its use, barriers, and promising data that suggest a single dose, which would ease finance and infrastructure requirements, may be sufficient.

Two doses of the HPV vaccines administered 6- to 12-months apart is the current recommendation for adolescents. What makes you think a single dose might be enough?
In the pre-licensure HPV vaccine trials, women were randomized to receive three doses of either the HPV vaccine or the control vaccine. Yet, not all women in the studies received all the doses. This enabled us to look at the efficacy of the HPV vaccines by number of doses received. We did this first in the Costa Rica HPV Vaccine Trial (CVT), which tested the bivalent HPV vaccine. We showed similar vaccine efficacy over four years among women who received one, two and three doses of the bivalent HPV vaccine. We also observed durable antibody responses in single-dose women, which suggested the observed efficacy may be real. Our confidence in this finding grew when similar results were observed in the industry-sponsored PATRICIA trial.

Of 88 proposed interventions, 16 were considered the most cost-effective and feasible for implementation-- vaccinating girls aged 9-13 years against HPV and screening women aged 30-49 years for cervical cancer made this important list.

We are also excited about the new 48-month data from an interrupted post-licensure trial in India that utilized the quadrivalent HPV vaccine. Again, similar protection against HPV16/18 cervical infection was observed regardless of number of vaccine doses. The compilation of the data is compelling and led us to hypothesize that one dose may be enough. Moreover, in the CVT long-term follow-up, we now have data out to seven years following initial vaccination showing that women who received only one dose of the HPV vaccine are still similarly protected against HPV16/18 infections as those who received two or three doses.

So, what is some of the newest research that will test the hypothesis that onedose of the HPV vaccines may provide durable protection?
Several new trials have been initiated to directly evaluate the hypothesis of the protection afforded by one-dose schedules of the HPV vaccines. The US NCI, again in collaboration with the Costa Rica Agencia Costarricense de Investigaciones Biomédicas, will conduct a large, 20,000 subject, randomized, controlled, trial (ClinicalTrials.gov identifier: NCT03180034; PIs: Aimée R Kreimer and Paula Gonzalez) in Costa Rica, with two of the licensed HPV vaccines: the first-generation bivalent vaccine Cervarix® (GlaxoSmithKline [GSK]) and the second-generation nonavalent vaccine Gardasil9® (Merck). The main goals of the trial are to evaluate whether, in adolescent girls, one dose or two doses of the bivalent or nonavalent vaccines can confer strong, durable protection against persistent HPV infections. Virologic endpoints are necessary in the evaluation of a one-dose schedule, as the antibody levels are inferior to that of two doses, and, as yet, we do not know the minimum level required for protection. Separately for each vaccine, onedose will be compared to the two-dose regimen in a formal randomized trial. Analyses will also be conducted to estimate vaccine efficacy versus no vaccination using a concurrent population survey of comparable, unvaccinated age-matched females in the same region, who will be tested for HPV DNA and then immediately vaccinated. The trial is intended to provide the level of proof required to modify public health policies.

Complementary to this large effort are three immunogenicity trials. The first is the DORIS trial in Tanzania (PI: Deborah Watson-Jones). This study will randomize 900 girls to six arms (one, two and three doses of the bivalent or nonavalent HPV vaccines). Girls in this trial will be followed for three years and will have blood collected and tested for HPV antibody levels. The main goal is to document non-inferiority of HPV seropositivity comparing girls who received one to three doses. In the Gambia a similar study is being implemented using the nonavalent HPV vaccine only, which will also look at reduced dose schedules in younger females (PI: Ed Clarke). Finally, there is a US-based HPV vaccine trial that aims to evaluate a two-year deferred dosing schedule, but in doing so, will also be able to assess short-term HPV antibody levels among girls and boys who received one dose of the nonavalent HPV vaccine (Protocol Co-PIs: Anna-Barbara Moscicki and Yi Zeng). Several immunobridging studies are planned with these immunogenicity-only studies, in that serology samples from the trials will be tested with samples from the existing and new Costa Rica HPV vaccine trials. If one-dose protection is documented using virologic endpoints in the Costa Rica trial for either or both HPV vaccines, and non-inferiority in antibody levels is observed in immunogenicity studies, we can immunobridge the efficacy findings in the Costa Rica study to other populations around the world.

We will also continue to follow the initial one-dose women from Costa Rica, as the India study will as well, so that the field can continue to investigate and document the duration of protection from a onedose regimen.

What will the audience of HPV WORLD read about in this issue?
First, Dr. Bruni will share her newest data on the uptake of HPV vaccination by world region. Despite these vaccines being initially approved more than a decade ago, less than 10% of adolescent girls have been vaccinated, even with a single dose. She also points out that the world regions with the greatest cervical cancer disease burden have introduced HPV vaccination to a lesser degree. Next, Drs. LaMontagne, Gallagher and Watson-Jones provide context for the perceived lag in HPV vaccine uptake, and challenge us to consider key issues related to broad vaccine implementation. Importantly, the authors contrast HPV vaccine uptake with that of other recent vaccines, and present ongoing barriers. As price remains an important consideration, adoption of a one-dose HPV vaccination schedule may be part of the solution.

We then move on to multiple articles focused on the biological rationale and existing evidence around the protection afforded by onedose HPV vaccination. Dr. Schiller presents, from both the immunologic and virologic perspectives, the rationale why onedose of a subunit vaccination may actually work, challenging the current science that a prime-boost regimen is required for durable immunity. Then, Drs. Sankaranarayanan, Gonzalez and colleagues present non-randomized data from phase 3 trials on the efficacy/effectiveness of one-dose regimens- these are the main data that continue to drive the field towards the continued evaluation of single dose HPV regimens. Drs. Brisson, Drolet and Markowitz present post-licensure vaccine effectiveness data, by number of doses received, from national immunization programs. Critical insights on vaccine protection for the recommended dosing regimen have been garnered using post-licensure data. Yet, the authors present important caveats to using these data sources for understanding dose-stratified, individual-level efficacy, given the biases present in the reduced-dose recipients and the complexities in the analysis to control for prevalent HPV infections at time of initial vaccination.

Dr. Kim then addresses the important question: what if a single dose isn’t as good as two doses? She uses modeling to inform population-level reductions in HPV prevalence under varying scenarios of an inferior onedose HPV vaccine. Based on her work, there are multiple aspects of a vaccine program that can compensate for reduced efficacy- this is especially true when the comparison is reframed to illustrate the potential gains from one-dose HPV vaccine introduction can be compared to no HPV vaccination.

Moreover, in the CVT longterm follow-up, we now have data out to seven years following initial vaccination showing that women who received only one dose of the HPV vaccine are still similarly protected against HPV16/18 infections as those who received two or three doses.

This issue closes with Drs. Shiffman and Wentzensen discussing opportunities to merge single-dose HPV vaccination with HPV screen and treat approaches (see the previous issue of HPVWORLD for a reminder), and with Dr. Dull presenting the perspective from the Bill & Melinda Gates Foundation for accelerating the potential HPV vaccine impact.

One overarching goal for the HPV vaccine research community is to generate evidence that will translate to expanded access to this vaccine. The compilation of articles in this issue of HPV WORLD highlights the collaborative efforts of our scientists moving toward this shared goal of faster cervical cancer eradication. I hope you enjoy reading this issue of HPV WORLD as much as we enjoyed writing it!

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INTERVIEW WITH
Aimée R. Kreimer, PhD
Senior Investigator, Infections & Immunoepidemiology Branchl
Bethesda, MD, United States

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