The Long Road Toward COVID-19 Herd Immunity: Vaccine Platform Technologies and Mass Immunization Strategies

Abstract

There is an urgent need for effective countermeasures against the current emergence and accelerating expansion of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Induction of herd immunity by mass vaccination has been a very successful strategy for preventing the spread of many infectious diseases, hence protecting the most vulnerable population groups unable to develop immunity, for example individuals with immunodeficiencies or a weakened immune system due to underlying medical or debilitating conditions. Therefore, vaccination represents one of the most promising counter-pandemic measures to COVID-19. However, to date, no licensed vaccine exists, neither for SARS-CoV-2 nor for the closely related SARS-CoV or Middle East respiratory syndrome-CoV. In addition, a few vaccine candidates have only recently entered human clinical trials, which hampers the progress in tackling COVID-19 infection. Here, we discuss potential prophylactic interventions for SARS-CoV-2 with a focus on the challenges existing for vaccine development, and we review pre-clinical progress and ongoing human clinical trials of COVID-19 vaccine candidates. Although COVID-19 vaccine development is currently accelerated via so-called fast-track programs, vaccines may not be timely available to have an impact on the first wave of the ongoing COVID-19 pandemic. Nevertheless, COVID-19 vaccines will be essential in the future for reducing morbidity and mortality and inducing herd immunity, if SARS-CoV-2 becomes established in the population like for example influenza virus.

Keywords: COVID-19; SARS-CoV-2; animal models; coronavirus; herd immunity; immune response; immunopathology; vaccine.

Figure 1

The genome, virion, and replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). (A) Schematic diagram of the SARS-CoV-2 genome. Approximately two-thirds of the positive single stranded RNA genome encodes a large polyprotein (ORF1a/b; nude). The last third of the genome proximal to the 3′-end encodes four structural proteins, i.e., the spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins (red, orange, green, and blue, respectively). The colors of the structural proteins are consistent in this figure. (B) Schematic diagram of the SARS-CoV-2 virion. The virion displays a nucleocapsid composed of genomic RNA (+ssRNA) and N protein, which is enclosed inside the virus envelope consisting of S, E, and M proteins. (C) Schematic overview of the life cycle of SARS-CoV-2 in host cells. The life cycle is initiated upon binding of the S protein to angiotensin-converting enzyme 2 (ACE2) on host cells, e.g., epithelial cells in the alveoli. After receptor binding, a conformational change in the S protein facilitates viral endocytosis and envelope fusion with the cell membrane. Subsequently, viral genomic RNA is released into the host cell, and viral +ssRNA is translated into viral polymerase encoded by the genome, which initiates replication of +ssRNA to –ssRNA and further produces a series of genomic and subgenomic mRNAs. These are translated into viral proteins, which are subsequently assembled with genomic RNA into virions in the endoplasmic reticulum (ER) and the ER-Golgi intermediate compartment (ERGIC) to form mature virions that are trafficked via Golgi vesicles out of the cell by exocytosis. Created with Biorender.com.

Figure 2

Host immune response and immunopathology during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. SARS-CoV-2 infects cells expressing the surface receptors angiotensin- converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). SARS-CoV-2 dampens anti-viral type I IFN responses, which results in uncontrolled viral replication. Viral pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) activate epithelial cells, endothelial cells, and tissue-resident macrophages to release proinflammatory cytokines and chemokines, including interleukin 6 (IL-6), IFN gamma-induced protein 10 (IP-10), IFN gamma (IFN-γ), IL-2, IL-10, macrophage inflammatory protein 1α (MIP1α), MIP1β, monocyte chemoattractant protein 1 (MCP1), granulocyte colony-stimulating factor (G-CSF), and tumor necrosis factor alpha (TNF-α). Cytokine- and chemokine-activated macrophages and virus-infected dendritic cells mediate extensive production of additional cytokines and chemokines, which eventually initiates a so-called cytokine storm. Chemokines attract more inflammatory cells that migrate from the blood vessels into the lungs, and these cells intensify the cytokine storm by releasing additional proinflammatory chemokines and cytokines, hence establishing a proinflammatory feedback loop. The cytokines circulate to other organs via the blood, eventually causing multi-organ damage. The downstream production of the cytokines IL-6 and IL-1β recruits neutrophils and CD8⁺ T cells, which not only control viral growth but also induce tissue damage, leading to alveolar flooding and consolidation (acute respiratory distress syndrome). IL-6 may recruit T-helper type 17 cells (Th17), which exacerbate inflammatory responses following activation. IL-6 also recruits follicular helper T cells (T_FH) and B cells/plasma cells, which produce SARS-CoV-2-specific antibodies that may help virus neutralization. Alternatively, B cells produce non-neutralizing antibodies that enhance SARS-CoV-2 infection through antibody-dependent enhancement, which further exacerbate organ damage. Created with Biorender.com.

Figure 3

Examples of COVID-19 vaccine candidates in (A) preclinical (n = 62) and (B) clinical development (n = 15), grouped according to vaccine platform technology.