Vaccine-enhanced disease: case studies and ethical implications for research and public health

Abstract

Vaccination is a cornerstone of global public health. Although licensed vaccines are generally extremely safe, both experimental and licensed vaccines are sometimes associated with rare serious adverse events. Vaccine-enhanced disease (VED) is a type of adverse event in which disease severity is increased when a person who has received the vaccine is later infected with the relevant pathogen. VED can occur during research with experimental vaccines and/or after vaccine licensure, sometimes months or years after a person receives a vaccine. Both research ethics and public health policy should therefore address the potential for disease enhancement. Significant VED has occurred in humans with vaccines for four pathogens: measles virus, respiratory syncytial virus, Staphylococcus aureus, and dengue virus; it has also occurred in veterinary research and in animal studies of human coronavirus vaccines. Some of the immunological mechanisms involved are now well-described, but VED overall remains difficult to predict with certainty, including during public health implementation of novel vaccines. This paper summarises the four known cases in humans and explores key ethical implications. Although rare, VED has important ethical implications because it can cause serious harm, including death, and such harms can undermine vaccine confidence more generally – leading to larger public health problems. The possibility of VED remains an important challenge for current and future vaccine development and deployment. We conclude this paper by summarising approaches to the reduction of risks and uncertainties related to VED, and the promotion of public trust in vaccines.

Vaccine-associated enhanced disease in humans and animal models: Lessons and challenges for vaccine development

“…Investigation of the possibility of VAED is crucial during clinical trials for decision-making on vaccine licensing by regulatory agencies. To minimize risks for the participants, compromises have to be made between the scientific interests of the trial and the safety of the participants ( Jamrozik et al, 2021a ). For example, Phase III clinical trials that test for efficacy should involve a rigorous selection of participants in areas with a higher probability of encountering the virus to reduce the required time and hence the cost of the trial, but for whom the outcome of potential VAED would not be as severe.…”

“…With the exception of the anti-DENV vaccine developed by Sanofi Pasteur and the FI-MV vaccine, which were withdrawn from the market, the occurrence of VAED has always been detected during preclinical and clinical experimental phases (i.e., before licensing) ( Jamrozik et al, 2021a ). However, continued safety monitoring is carried out even after marketing to ensure the benefits of the vaccines.…”

“…In certain circumstances, the immune responses triggered by exposure to antigens can, individually or through their association, favor exacerbated disease upon subsequent exposure to that same pathogen. Although this process has been described to occur naturally in the case of dengue virus (DENV) after sequential exposition to different serotypes ( Halstead, 2007 ; Guzman et al, 2013 ), vaccination against most infectious diseases has resulted in only very rare cases of VAED ( Huisman et al, 2009 ; Jamrozik et al, 2021a ; Munoz et al, 2021 ). In the few reported cases, the enhanced disease was due to failed efforts of the immune system to control the infection and subsequently manifested with symptoms related to the organ(s) targeted by the virus.…”

“…These vaccine candidates and approved vaccines are based on different platforms and formulations, but most target the Spike protein (WHO, 2020;Covid-19 Vaccine, 2022). There were initial concerns about the possibility that the new SARS-Cov-2 vaccines may carry a risk of VAERD (Arvin et al, 2020;Halstead, 2021;Jamrozik et al, 2021a;Munoz et al, 2021;Gartlan et al, 2022), but two years of epidemiological data in clinical trials and widespread administration of these vaccines in the general population have made it possible to alleviate them. These concerns were based on several observations, a number of which are mentioned below:…”

“…Understanding and controlling the immune mechanisms elicited by such vaccines is crucial in moving forward in this quest. Beyond the fear of developing an ineffective vaccine, a concern ( Graham, 2020 ) in the field of vaccinology is the formulation of vaccines that, upon subsequent natural infection, may intensify the severity and worsen the prognosis of the pathology they were designed to protect against; a process known as a vaccine-associated enhanced disease (VAED) ( Huisman et al, 2009 ; Jamrozik et al, 2021a ; Munoz et al, 2021 ). More specifically, VAED is defined in this review as the immune-mediated aggravation of the clinical course of infection following immunization relative to that in the absence of previous vaccination.…”