Beyond clinical trials: Evolutionary and epidemiological considerations for development of a universal influenza vaccine

Abstract

The prospect of universal influenza vaccines is generating much interest and research at the intersection of immunology, epidemiology, and viral evolution. While the current focus is on developing a vaccine that elicits a broadly cross-reactive immune response in clinical trials, there are important downstream questions about global deployment of a universal influenza vaccine that should be explored to minimize unintended consequences and maximize benefits. Here, we review and synthesize the questions most relevant to predicting the population benefits of universal influenza vaccines and discuss how existing information could be mined to begin to address these questions. We review three research topics where computational modeling could bring valuable evidence: immune imprinting, viral evolution, and transmission. We address the positive and negative consequences of imprinting, in which early childhood exposure to influenza shapes and limits immune responses to future infections via memory of conserved influenza antigens. However, the mechanisms at play, their effectiveness, breadth of protection, and the ability to "reprogram" already imprinted individuals, remains heavily debated. We describe instances of rapid influenza evolution that illustrate the plasticity of the influenza virus in the face of drug pressure and discuss how novel vaccines could introduce new selective pressures on the evolution of the virus. We examine the possible unintended consequences of broadly protective (but infection-permissive) vaccines on the dynamics of epidemic and pandemic influenza, compared to conventional vaccines that have been shown to provide herd immunity benefits. In conclusion, computational modeling offers a valuable tool to anticipate the benefits of ambitious universal influenza vaccine programs, while balancing the risks from endemic influenza strains and unpredictable pandemic viruses. Moving forward, it will be important to mine the vast amount of data generated in clinical studies of universal influenza vaccines to ensure that

Economic and Behavioral Influencers of Vaccination and Antimicrobial Use

“…Current vaccination strategies elicit immune responses to exposed HA regions that are known targets of antibodies (145), but only have moderate efficacy (146). To further increase immunity in human populations and reduce the number of necessary vaccines to maintain herd immunity, there are currently significant efforts aimed at developing and understanding the impact of Universal Influenza Vaccines (UIVs) that would provide broad protection across multiple strains for multiple years (147)(148)(149).…”

T Cell Immunity against Influenza: The Long Way from Animal Models Towards a Real-Life Universal Flu Vaccine

“…As pointed out by others, one result could be a general decrease of flu infections, while decreasing virus replication per person is also slowing down virus evolution. On the other hand, immune pressure on conserved virus proteins exceeding natural immunity could select for escape mutants [ 176 ]. However, viral escape might be limited due to functional constraints and loss of viral fitness [ 57 ].…”

Mosaic vaccination: how distributing different vaccines across a population could improve epidemic control

“…Therefore, there are two possibilities: if R 0 ≤ 1, U (∞) = U (0), otherwise U (∞) is the solution of equation 18satisfying 0 < U (∞) < U (0). Once we have U (∞), we can then plug it into equation (12) to obtain S(∞).…”

“…In particular, the search for more highly conserved targets of immune responses may yet produce a universal vaccine that need not be updated in the face of antigenic evolution [8][9][10][11]. Yet the consequences of such vaccines, including for pathogen evolution, have not been fully elucidated [12]. An alternative strategy is a vaccine cocktail, designed to elicit immune responses against multiple targets (i.e., epitopes) with a single vaccine [12]; much like drug cocktails, these are expected to be more robust in the face of evolution [13].…”

“…Yet the consequences of such vaccines, including for pathogen evolution, have not been fully elucidated [12]. An alternative strategy is a vaccine cocktail, designed to elicit immune responses against multiple targets (i.e., epitopes) with a single vaccine [12]; much like drug cocktails, these are expected to be more robust in the face of evolution [13].…”