Impact of virus genetic variability and host immunity for the success of COVID-19 vaccines

Abstract

Coronavirus disease 19 (COVID-19) continues to challenge most scientists in the search of an effective way to either prevent infection or to avoid spreading of the disease. As result of global efforts some advances have been reached and we are more prepared today than we were at the beginning of the pandemic, however not enough to stop the transmission, and many questions remain unanswered. The possibility of reinfection of recovered individuals, the duration of the immunity, the impact of SARS-CoV-2 mutations in the spreading of the disease as well as the degree of protection that a potential vaccine could have are some of the issues under debate. A number of vaccines are under development using different platforms and clinical trials are ongoing in different countries, but even if they are licensed it will need time until reach a definite conclusion about their real safety and efficacy. Herein we discuss the different strategies used in the development of COVID-19 vaccines, the questions underlying the type of immune response they may elicit, the consequences that new mutations may have in the generation of sub-strains of SARS-CoV-2 and their impact and challenges for the efficacy of potential vaccines in a scenario postpandemic.

Keywords: Long-term immunity; Mutation; Reinfection; Spike protein; T-cell response.

Graphical abstract

Fig. 1

Structure of SARS-CoV-2 showing the main structural proteins. The virus consists of four major structural proteins: spike (S), envelope (E), membrane (M) and nucleocapsid (N). S, E and M are located in the lipid bilayer envelope while the N protein encapsulates the virus RNA genome.

Fig. 2

Schematic diagram of SARS-CoV-2 genomic organization. The positive single stranded 5′ capped mRNA has a leader sequence (LS), poly-A tail at 3’ end, and 5’ and 3’ UTR. The genome comprises ORF1a, ORF1b, Spike (S), ORF3a,b, Envelope (E), Membrane (M), ORF6, ORF7a, ORF7b, ORF8, Nucleocapsid (N), ORF9 and ORF10. ORF1a and ORF1b cover the 5’ two-thirds of the genome and encode two large polyproteins, pp1a and pp1ab that are cleaved by papain-like cysteine protease (PLpro) and 3C-like serine protease (3CLpro) at the cleavage sites indicated by the black and grey triangles, into 16 non-structural proteins including the mentioned proteases, the RNA dependent RNA polymerase (RdRp), Helicase (Hel/MTase) and functional domains Exonuclease (ExonN), Endonuclease (Nendo U) and 2′-O-RNA methyltransferase (2`-O-MTase). The 3’ one-third end of the genome encodes the structural and accessory proteins.

Fig. 3

Immune response against SAR-CoV-2 infection. 1. SARS-CoV-2 infects ACE2 expressing target cells such as alveolar epitelial type 2 cells in the lungs. 2. Virus may overcome induced antiviral Interferon (IFN) responses leading to uncontrolled replication. 3. Neutrophils and monocytes/macrophages are recruited to the site of infection and may cause overproduction of pro-inflammatory cytokines such as IL-6, IL-8, IL-12,TNF-α and others, involved in the immunopathology of COVID-19 in the lungs known as “cytokine storm”. Both humoral and cellular immune responses are elicited. 4. Infected epithelial cells may present virus antigens to CD8 + T cells, which together with natural killers (NK) cells become cytotoxic to the virus-infected epithelial cells leading to apoptosis. 5. Dendrictic cells (DC) present virus antigen to CD4 + T cells and induce their differentiation into memory Th1 and Th17 as well as memory T follicular helper (TFH) effector CD4 + T cells. 6. Activated B-cells and plasma cells synthesize IgM, IgA and IgG anti- SARS-CoV-2 specific antibodies. 7. Macrophages and dendrict cells present antigens to CD4 + T cells via MHC-TCR interaction. 8. Memory T cells subset are produced and may provide immunity against reinfection with the same virus strain for a period still not well established.

Fig. 4

Different platforms used for development of COVID-19 vaccine. Classical and next generation platforms are currently being used to develop vaccines against SARS-CoV-2. Inactivated (1) and live attenuated vaccines (2) are classical platforms that uses the whole SARS-CoV-2 virus as vaccine. Since the viruses used to produce the vaccine do not replicate either by chemical inactivation or genetic modification, the vaccines require adjuvants to induce optimal immune response. Recombinant protein platform (3) uses a broad range of technologies to prepare viral proteins such as SARS-CoV-2 Spike, as imunogen to induce immune response. Viral-like particles platform (VLPs) (4) are example of new technology platform and contain copies of one or more viral proteins that assemble into nanoparticles of 10-200 nm and are used as vaccine. DNA (5) and RNA (6) vaccines are also considered new generation platforms and consist of nucleic acids containing part of virus genetic material that can be delivered by electroporation intradermally or by lipid nanoparticles respectively. Inactivated adenoviral vectors (7), replication competent adenoviral vectors (8) and non replication competent adenoviral vectors (9) are known as viral-based vectors vaccine and use genetic modified adenovirus as vector to carry SARS-CoV-2 imunogenic protein coding sequences to induce immune response.