Limited available evidence supports theoretical predictions of reduced vaccine efficacy at higher exposure dose

Abstract

Understanding the causes of vaccine failure is important for predicting disease dynamics in vaccinated populations and planning disease interventions. Pathogen exposure dose and heterogeneity in host susceptibility have both been implicated as important factors that may reduce overall vaccine efficacy and cause vaccine failure. Here, we explore the effect of pathogen dose and heterogeneity in host susceptibility in reducing efficacy of vaccines. Using simulation-based methods, we find that increases in pathogen exposure dose decrease vaccine efficacy, but this effect is modified by heterogeneity in host susceptibility. In populations where the mode of vaccine action is highly polarized, vaccine efficacy decreases more slowly with exposure dose than in populations with less variable protection. We compared these theoretical results to empirical estimates from a systematic literature review of vaccines tested over multiple exposure doses. We found that few studies (nine of 5,389) tested vaccine protection against infection over multiple pathogen challenge doses, with seven studies demonstrating a decrease in vaccine efficacy with increasing exposure dose. Our research demonstrates that pathogen dose has potential to be an important determinant of vaccine failure, although the limited empirical data highlight a need for additional studies to test theoretical predictions on the plausibility of reduced host susceptibility and high pathogen dose as mechanisms responsible for reduced vaccine efficacy in high transmission settings.

Impact of Vaccination and Pathogen Exposure Dosage on Shedding Kinetics of Infectious Hematopoietic Necrosis Virus (IHNV) in Rainbow Trout

“…This suggests that at very high viral dosages, immunity provided by vaccination is diminished. These findings agree with the findings of others that increasing pathogen dosage leads to increased infection probability and reduced vaccine efficacy, although studies are limited and the shape of the relationship varies between systems (Gomes et al 2014;Langwig et al 2017Langwig et al , 2019. A few studies have investigated whether the increase in probability of infection with pathogen exposure dosage is a function of simply more virus particles entering the host (independent action) or virus particles interacting in some way to enhance infection (mass action), such as through suppression or overwhelming of the immune system (Regoes et al 2003;Zwart et al 2011).…”

“…However, the results imply that vaccine protection may operate under a threshold, wherein high viral dosages will overwhelm reductions in the probability of infection due to vaccination, and that these reductions are not absolute. This has been observed in other systems (Langwig et al 2019) and could be a function of limits in the level of immune stimulation that vaccination can provide, such as antibody production. Examining vaccine efficacy at multiple vaccine dosages may shed light on this.…”

“…This is one of the first studies to investigate vaccine impacts on host mortality and virus shedding kinetics across multiple pathogen exposure dosages (as reviewed in Langwig et al 2019) and host lineages. The study provided an estimate of the efficacy of blocking transmission using vaccination under diverse conditions, which may be encountered in the field.…”

“…For example, transmission from vaccinated hosts to unvaccinated hosts was documented in vaccinated baboons exposed to Pertussis (Warfel et al 2014), in Atlantic Salmon Salmo salar exposed to infectious hematopoietic necrosis virus (IHNV; Long et al 2017), and in case-control studies using live, attenuated oral polio vaccines (Sutter et al 1991). Additionally, protection under diverse conditions commonly observed in the field, such as variable pathogen exposure dosages, is not fully understood (Langwig et al 2019). Recent studies have indicated that vaccine efficacy is pathogen dose dependent, particularly in the context of preventing transmission (i.e., transmission blocking: Gomes et al 2014;Langwig et al 2017).…”

Prioritizing second-generation SARS-CoV-2 vaccines through low-dosage challenge studies

“…Low-dosage challenges may therefore be less liable to prematurely rule out vaccines with some degree of efficacy (that is, less liable to a type II error). Based on limited evidence, some vaccines seem to prevent infection via small viral exposures, yet fail against larger viral exposures (Langwig et al, 2019). A vaccine that prevents a significant fraction of community-acquired infections would have powerful herd immunity effects if widely administered, even if it were less efficacious at preventing (higher-dosage) infection or severe disease.…”