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. 2021 Mar;19(3):211-219.
doi: 10.1038/s41579-020-00462-y. Epub 2020 Oct 16.

Learning from the past: development of safe and effective COVID-19 vaccines

Shan Su  1 , Lanying Du  2 , Shibo Jiang  3   4
Affiliations

Learning from the past: development of safe and effective COVID-19 vaccines

Shan Su et al. Nat Rev Microbiol. 2021 Mar.

Abstract

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has elicited an equally rapid response aiming to develop a COVID-19 vaccine. These efforts are encouraging; however, comprehensive efficacy and safety evaluations are essential in the development of a vaccine, and we can learn from previous vaccine development campaigns. In this Perspective, we summarize examples of vaccine-associated disease enhancement in the history of developing vaccines against respiratory syncytial virus, dengue virus, SARS-CoV and Middle East respiratory syndrome coronavirus, which highlight the importance of a robust safety and efficacy profile, and present recommendations for preclinical and clinical evaluation of COVID-19 vaccine candidates as well as for vaccine design and optimization.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Mechanisms of vaccine-associated disease enhancement.
Vaccination induces humoral and cellular immune response in immunized individuals. In the normal condition, when the homologous virus enters an immunized body, it will be neutralized or cleared by vaccine-induced neutralizing antibodies (Abs) or specific T cells, respectively. In the context of vaccine-associated disease enhancement, vaccines mainly induce non-neutralizing Abs or low titres of neutralizing Abs (suboptimal concentration) or type 2 T helper cell (TH2 cell)-biased T cell responses. When these vaccinated individuals are challenged by homotypic or heterotypic serotype viruses, the antibodies will immediately recognize the viruses and mediate antibody-dependent disease exacerbation in two ways. First, virus–antibody complexes might enter Fc receptor (FcR)-bearing cells, such as dendritic cells and monocytes, by FcR-mediated internalization, which is termed ‘antibody-dependent enhancement’ (ADE). For viruses with innate tropism for FcR-bearing cells, such as dengue virus, ADE will result in higher viral loads than in conditions without antibodies. a | After entry, the virus, no matter whether it replicates or does not replicate, may activate a harmful immune response, resulting in the release of proinflammatory cytokines. b | Aside from ADE, antibody–antigen complexes can stimulate the complement pathway through activation of the C1q pathway, thus further strengthening the inflammatory responses c | Vaccine-associated disease enhancement can also involve a TH2 cell-biased immune response. The activated TH2 cells contribute to the activation of antibody production. However, they release interleukin-4 (IL-4), IL-13 and IL-5, as well as eosinophil chemoattractant, thus resulting in eosinophil infiltration and proinflammatory cytokine production in the lung. d | Natural killer (NK) cells and CD8+ cytotoxic T lymphocytes (CTLs) are poorly stimulated in TH2 cell-skewed immune responses. The exaggerated cytokine release (part b), activation of the complement pathway (part c) and the excessive mobilization of eosinophils all contribute to the infiltration of the lung by eosinophils, neutrophils and lymphocytes, and production of inflammatory cytokines (part d), leading to acute lung injury or acute respiratory distress syndrome.
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