Assessing Population-level Target Product Profiles of Broadly-protective Human Influenza A Vaccines

Influenza A has two main clades, with stronger cross-immunity to reinfection within than between clades. Here, we explore the implications of this heterogeneity for proposed cross-protective influenza vaccines that may offer broad, but not universal, protection. While the development goal for the breadth of human influenza A vaccine is to provide cross-clade protection, vaccines in current development stages may provide better protection against target clades than non-target clades. To evaluate vaccine formulation and strategies, we propose a novel perspective: a vaccine population-level target product profile (PTPP). Under this perspective, we use dynamical models to quantify the epidemiological impacts of future influenza A vaccines as a function of their properties. Our results show that the interplay of natural and vaccine-induced immunity could strongly affect seasonal clade dynamics. A broadly protective bivalent vaccine could lower the incidence of both clades and achieve elimination with sufficient vaccination coverage. However, a univalent vaccine at low vaccination rates could permit a resurgence of the non-target clade when the vaccine provides weaker immunity than natural infection. Moreover, as a proxy for pandemic simulation, we analyze the invasion of a variant that evades natural immunity. We find that a future vaccine providing sufficiently broad and long-lived cross-clade protection at a sufficiently high vaccination rate, could prevent pandemic emergence and lower the pandemic burden. This study highlights that as well as effectiveness, breadth and duration should be considered in epidemiologically informed TPPs for future human influenza A vaccines. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded by FluLab. Q.Y. acknowledges funding from the Center for Health and Wellbeing, Princeton University, via Graduate Funding for Health-Focused Research. S.W.P. acknowledges funding from Princeton University via a Charlotte Elizabeth Procter Fellowship. C.M.S.-R. acknowledges funding from the Miller Institute for Basic Research in Science of UC Berkeley via a Miller Research Fellowship. B.T.G acknowledges support from Princeton Catalysis Initiative. The authors thank Bin Zhang for suggesting potential datasets. Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the US National Institutes of Health or Department of Health and Human Services. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced are available online at