Progress and Pitfalls in the Quest for Effective SARS-CoV-2 (COVID-19) Vaccines

Abstract

There are currently around 200 SARS-CoV-2 candidate vaccines in preclinical and clinical trials throughout the world. The various candidates employ a range of vaccine strategies including some novel approaches. Currently, the goal is to prove that they are safe and immunogenic in humans (phase 1/2 studies) with several now advancing into phase 2 and 3 trials to demonstrate efficacy and gather comprehensive data on safety. It is highly likely that many vaccines will be shown to stimulate antibody and T cell responses in healthy individuals and have an acceptable safety profile, but the key will be to confirm that they protect against COVID-19. There is much hope that SARS-CoV-2 vaccines will be rolled out to the entire world to contain the pandemic and avert its most damaging impacts. However, in all likelihood this will initially require a targeted approach toward key vulnerable groups. Collaborative efforts are underway to ensure manufacturing can occur at the unprecedented scale and speed required to immunize billions of people. Ensuring deployment also occurs equitably across the globe will be critical. Careful evaluation and ongoing surveillance for safety will be required to address theoretical concerns regarding immune enhancement seen in previous contexts. Herein, we review the current knowledge about the immune response to this novel virus as it pertains to the design of effective and safe SARS-CoV-2 vaccines and the range of novel and established approaches to vaccine development being taken. We provide details of some of the frontrunner vaccines and discuss potential issues including adverse effects, scale-up and delivery.

Keywords: Coalition for Epidemic Preparedness Innovations (CEPI); adverse events of special interest (AESI); antibody dependent enhancement (ADE); bacillus Calmette-Guérin (BCG); cell mediated immunity; innate immunity; neutralizing antibodies; spike protein.

Figure 1

Structure of SARS-CoV-2 and key antigenic components. Illustration of SARS-CoV-2 which is a single stranded RNA virus. The key antigenic components being targeted in vaccine design are shown on the right, consisting of the spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins. The main emphasis for human vaccines is based on the spike (S) protein, consisting of an S1 binding region and S2 fusion and cell entry region. The S1 domain contains the receptor binding domain (RBD) responsible for binding to the ACE2 receptor on the surface of host cells. Following fusion, the S protein sheds the S1 region and undergoes a dramatic structural change to its post-fusional state in order for the virus to enter the host cells.

Figure 2

Key components of the innate immune response to SARS-CoV-2. Antigen presenting cells (APCs), such as monocytes, macrophages, and dendritic cells (DCs), recognize pattern associated molecular patterns (PAMPs) expressed by SARS-CoV-2 via their pattern recognition receptors (PRRs), such as toll-like receptor (TLR) 3 and 7. This activates intracellular signaling pathways leading to the expression of type 1 and 3 interferons (IFNs), which in turn activate innate immune cells to produce pro-inflammatory cytokines and chemokines. This leads to an influx and activation of neutrophils, further APCs and other innate immune cells, such as natural killer (NK) cells.

Figure 3

Key components of the adaptive immune response to SARS-CoV-2. The adaptive immune response is activated following viral uptake and antigen processing by a range of APCs. The APCs present viral antigen to B cells which then differentiate into antibody producing plasma cells. The neutralizing antibodies (nAbs) then bind to key viral proteins, such as the spike protein, and neutralize their activity. Other Ab-mediated antiviral functions include antibody dependent cellular cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP), and antibody dependent complement activation (ADCA). Cytotoxic CD8⁺ T cells kill virally infected cells via the production of granzymes and perforin and the expression of Fas ligand (FasL), all of which mediate cellular apoptosis. A series of CD4⁺ T cell populations are involved in the adaptive cellular response to SARS-CoV-2. Follicular helper T cells (T_FH) and Th2 CD4⁺ T cells both provide help for B cell antibody production. Th1 and Th17 CD4⁺ T cells are also thought to play a role in the inflammatory response and viral killing. CD4⁺ regulatory T cells have been implicated with an immunoregulatory role in SARS-CoV-2 infection via the production of anti-inflammatory cytokines and contact-mediated cellular suppression. Whether CD8⁺ Tregs and Bregs play a role is not currently known.

Figure 4

Vaccine platforms being employed for SARS-CoV-2 vaccine design. This figure illustrates the different vaccine approaches being taken for the design of human SARS-CoV-2 vaccines. Whole virus vaccines include both attenuated and inactivated forms of the virus and subunits of inactivated virus can also be used. Protein and peptide subunit vaccines are usually combined with an adjuvant in order to enhance immunogenicity. The main emphasis in SARS-CoV-2 vaccine development has been on using the whole spike protein in its trimeric form or components of it, such as the RBD region. Multiple non-replicating viral vector vaccines have been developed, particularly focused on adenovirus; while there has been less emphasis on the replicating viral vector constructs. Nucleic acid-based approaches include DNA and mRNA vaccines, often packaged into nanocarriers such as virus-like particles (VLPs) and lipid nanoparticles (LNPs). Nanoparticle and VLP vaccines can also have antigen attached to their surface or combined in their core. The immune cell therapy approach uses genetically modified SARS-CoV-2-specific cytotoxic T cells and dendritic cells expressing viral antigens to protect against SARS-CoV-2 infection. Each of these vaccine approaches has benefits and disadvantages in terms of cost and ease of production, safety profile and immunogenicity, and it remains to be seen which of the many candidates in development protect against COVID-19.