COVID-19 Pandemic and Vaccines Update on Challenges and Resolutions

Abstract

The coronavirus disease (COVID-19) is caused by a positive-stranded RNA virus called severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), belonging to the Coronaviridae family. This virus originated in Wuhan City, China, and became the cause of a multiwave pandemic that has killed 3.46 million people worldwide as of May 22, 2021. The havoc intensified with the emergence of SARS-CoV-2 variants (B.1.1.7; Alpha, B.1.351; Beta, P.1; Gamma, B.1.617; Delta, B.1.617.2; Delta-plus, B.1.525; Eta, and B.1.429; Epsilon etc.) due to mutations generated during replication. More variants may emerge to cause additional pandemic waves. The most promising approach for combating viruses and their emerging variants lies in prophylactic vaccines. Several vaccine candidates are being developed using various platforms, including nucleic acids, live attenuated virus, inactivated virus, viral vectors, and protein-based subunit vaccines. In this unprecedented time, 12 vaccines against SARS-CoV-2 have been phased in following WHO approval, 184 are in the preclinical stage, and 100 are in the clinical development process. Many of them are directed to elicit neutralizing antibodies against the viral spike protein (S) to inhibit viral entry through the ACE-2 receptor of host cells. Inactivated vaccines, to the contrary, provide a wide range of viral antigens for immune activation. Being an intracellular pathogen, the cytotoxic CD8⁺ T Cell (CTL) response remains crucial for all viruses, including SARS-CoV-2, and needs to be explored in detail. In this review, we try to describe and compare approved vaccines against SARS-CoV-2 that are currently being distributed either after phase III clinical trials or for emergency use. We discuss immune responses induced by various candidate vaccine formulations; their benefits, potential limitations, and effectiveness against variants; future challenges, such as antibody-dependent enhancement (ADE); and vaccine safety issues and their possible resolutions. Most of the current vaccines developed against SARS-CoV-2 are showing either promising or compromised efficacy against new variants. Multiple antigen-based vaccines (multivariant vaccines) should be developed on different platforms to tackle future variants. Alternatively, recombinant BCG, containing SARS-CoV-2 multiple antigens, as a live attenuated vaccine should be explored for long-term protection. Irrespective of their efficacy, all vaccines are efficient in providing protection from disease severity. We must insist on vaccine compliance for all age groups and work on vaccine hesitancy globally to achieve herd immunity and, eventually, to curb this pandemic.

Keywords: COVID-19; SARS CoV-2 variant; booster dose; immune response; multivariant vaccines; mutations; spike protein; vaccine.

Figure 1

SARS-CoV-2 genome, encoded proteins, and basic mechanism of virus fusion and entry. (A) Illustration of the SARS-CoV-2 genome that is around 30 kb in size and has a 5’ cap and 3’ poly A tail. (B) SARS-CoV-2 proteins: nonstructural proteins (Nsp), ORF1a, and ORF1b (Nsp1-Nsp16) and structural proteins such as spike (S), envelope (E), membrane (M), and nucleocapsid (N) with spike protein having 1273 aa (~180 kDa) containing signal peptide (SP), N-terminal domain (NTD), receptor binding motif (RBM) in receptor binding domain (RBD), fusion peptide (FP), heptad repeat (HR)-1, HR-2, transmembrane domain (TM), and cytoplasmic tail (CP) domains. There are accessory proteins Orf3; Orf6,7,8,9; and Orf10 located in between the S, E, M, and N proteins. (C) The spike protein subunit 1 (S1; aa 14-685) of SARS-CoV-2 consists of the RBD domain divided into two parts: S1 N-terminal domain (S1-NTD) and S1 C-terminal domain (S1-CTD) and spike protein subunit 2 (S2; aa 686-1273) containing TM and CP domains. S1-CTD interacts with the angiotensin-converting enzyme-2 (ACE-2) receptor of host cells and facilitates fusion and entry of virus. The neutralizing antibody against S1-CTD blocks the entry of the SARS-CoV-2 into host cells. ORF1a; Open reading frame 1a, ORF1b; Open reading frame 1b, aa; Amino acid.

Figure 2

Strategies being utilized to develop vaccine candidates against SARS-CoV-2: A concise overview of various aspects of the SARS-CoV-2 vaccine development process varying from traditional to novel platforms. (A) Attenuated live pathogen vaccine: A debilitated (infection incompetent) form of the live pathogen obtained by lengthy cell culture passaging in nonhuman cell lines or animals are administered. (B) Protein subunit vaccines are prepared from either antigen purification of pathogens replicated in cell cultures or recombinant expressed antigens. (C, D) Nucleic acid vaccines: mRNA (C) or DNA (D) codifying for an immunogenic protein of the pathogen express and present the antigen in antigen-presenting cells. The mRNA is mixed with nanoparticles or other stabilizing agents, and DNA is inserted in a vector. (E) Viral vector vaccines: Recombinant viral vectors are produced by genetic manipulation of measles or the adenoviral platform to express the antigen of interest. (F) Inactivated pathogen vaccines contain the whole pathogen that has been subjected to heat or chemical treatment for inactivation. (G) Virus-like particles vaccines: These are virus-like particles (20–200 nm) assembled and released by many baculoviruses or the mammalian expression system, e.g., recombinant yeast cells, vaccinia virus expression system, or even tobacco plants transfected with tobacco mosaic virus platform.

Figure 3

Summary and number distribution of candidate vaccines in preclinical and clinical trials: (A) Clinical stages of candidate vaccines: Number of vaccines under clinical (depicted by orange color; 100) and preclinical development (depicted by blue color; 184). (B) Candidate vaccines of different platforms under clinical trial from bottom to top: Protein Subunit, VVnr, DNA, Inactivated Virus, RNA, VVr, VLP, BVr, LAV, Cell based and LABv with their respective candidate vaccine numbers. (C) Candidate vaccines of various platforms and their numbers under clinical phase 1, 2, or III: Phase-wise distribution along with the numbers in the platform used are marked in the bar graph. (D) Summary of various vaccines’ clinical trial status is presented in the graph: Vaccine production from inception to commercialization is a prolonged process that requires multiple clinical trials, some of which have failed due to adverse effects.

Figure 4

Overview of immune response elicited by various vaccine candidates. When administered into skin or muscle cells (A), the nucleic acid expresses and codes for an immunogenic protein that mimics viral infection (B). (C–E) Humoral responses: Antigens produced by skin/muscle cells are released in blood to activate the antibody response; antigen recognition by naïve B cells (C) leading to clonal selection and plasma cell (antibody secreting B cells) formation (D) and eventually production of long-lasting memory B cells (E). (F) Antigen processing and presentation: The antigen produced by skin/muscle cells are captured by antigen-presenting cells (APCs; dendritic cells or macrophages) for processing and presented by MHC-II or MHC-I molecules on their surface. (G–I) CD4⁺T helper cells effector and memory response: The presented MHC-II molecule and antigen complex on APCs recognized by TCR and CD4 molecules on CD4⁺ Th cells (G) leading to production of effector CD4⁺ Th cells (H), which produce sufficient levels of cytokines (Th2 cells produce TH2 cytokines IL-4 or IL-10 for humoral response and Th1 cells produce IL-12, IFN-Y for CTL response), and eventually, long-lasting memory CD4⁺ cells are generated (I). (J–L) CD8⁺T helper cells effector and memory response: The presented antigen and MHC-II molecule complex on APCs recognized by TCR and CD8 molecules on CD8⁺ T cells (J) leading to production of effector CD8⁺T cells also known as cytotoxic T lymphocytes (CTL), which are responsible for killing the infected or self-altered cells (K), and finally, long-lasting memory CD8⁺T cells are generated (L). All memory cells provide long-lasting, heightened, and antigen-specific responses upon future infections.

Figure 5

Antibody response to first, second, and probable third/annual booster dose of COVID-19 vaccination or infection: Initially, just after the first immunization, the vaccine does not elicit sufficient neutralizing antibody to prevent the infection of SARS-CoV-2. Upon administration of the second booster dose of vaccine, the vaccine elicits a stronger neutralizing antibody response with high titer that could prevent the infection efficiently. In some cases, third or annual boosters are required to revive the immune response against the pathogen.

Figure 6

Challenges in developing vaccines against SARS-CoV-2 (black color text), their description (red color text) and their possible resolutions (green color text). (A) Mutation in viral genome: The RNA viruses including SARS-CoV-2 are more prone to mutation in their genome, leading to viral immune evasion. (B) Cytokine storm during COVID-19 vaccination: Occasionally, the vaccination may lead to cytokine storm and other complications raised by it. (C) Lack of memory response: Any vaccine provides long-lasting efficacy only because of memory responses of adaptive immunity. No vaccine against SARS-CoV-2 is documented to have established memory response postvaccination. The neutralizing antibody fades away a few months post vaccination. (D) Antibody-dependent enhancements: There is the possibility of an antibody-mediated increase in infection called antibody dependent enhancement.