Question

Case study: SARS-CoV-2

a) Define the terms R₀ and case fatality rate,

b) Discuss the factors that influence the case fatality rate.

c) Discuss how SARS-CoV-2 enters human cells, the antigenic target of vaccine approaches and the immune response they aim to induce, and how this would protect against infection.

Answer 1

a) R0 represents the average number of susceptible individuals an infected person will transmit the disease to.

R0 = Attack rate x Contacts

Attack rate (the percent chance that a contact will get the disease).

If the R0 is < 1, a disease outbreak should wane over time, and if its >1, cases would continue to increase.

In epidemiology, a case fatality rate — sometimes called case fatality risk — is the proportion of deaths from a certain disease compared to the total number of people diagnosed with the disease for a certain period of time.

b) The likelihood that a person will die of SARS could be influenced by factors related to the SARS virus, the route of exposure and dose (amount) of virus, personal factors such as age or the presence of another disease, and access to prompt medical care.

c) COVID-19 is caused by SARS-CoV-2, a new type of coronavirus in the same genus as SARS-CoV and MERS-CoV. Viral proteins responsible for SARS-CoV-2 entry into host cells and replication are structurally similar to those associated with SARS-CoV. Thus, research and development on SARS and MERS may offer insights that would be beneficial to the development of therapeutic and preventive agents for COVID-19.

The development of attenuated-virus vaccines is also possible by carefully screening the serially propagated SARS-CoV-2 with reduced pathogenesis such as induced minimal lung injury, diminished limited neutrophil influx, and increased anti-inflammatory cytokine expressions compared with the wild-type virus. Both inactivated and attenuated virus vaccines have their own disadvantages and side effects. Alternatively, new vaccine designs based on the putative protective antigen/peptides derived from SARS-CoV-2 should be considered. SARS-CoV-2, which is similar to SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), is an enveloped, single- and positive-stranded RNA virus with a genome comprising 29,891 nucleotides, which encode the putative open reading frames responsible for the synthesis of viral structural and nonstructural proteins. A mature SARS-CoV-2 has four structural proteins, namely, envelope (E), membrane (M), nucleocapsid (N), and spike (S). All these proteins may serve as antigens to stimulate neutralizing antibodies and increase CD4+/CD8+ T-cell responses. However, subunit vaccines require multiple booster shots and suitable adjuvants to work, and certain subunit vaccines such as hepatitis B surface antigen, PreS1, and PreS2 may fail to yield protective response when tested clinically. The DNA and mRNA vaccines that are easier to design and proceed into clinical trials very quickly remain experimental. The viral vector-based vaccines could also be quickly constructed and used without an adjuvant. However, development of such vaccines might not start until antigens containing the neutralizing epitopes are identified.

The E and M proteins have important functions in the viral assembly of a coronavirus, and the N protein is necessary for viral RNA synthesis. Deletion of E protein abrogated the virulence of CoVs, and several studies have explored the potential of recombinant SARS-CoV or MERS-CoV with a mutated E protein as live attenuated vaccines. The M protein can augment the immune response induced by N protein DNA vaccine against SARS-CoV; however, the conserved N protein across CoV families implies that it is not a suitable candidate for vaccine development, and the antibodies against the N protein of SARS-CoV-2 do not provide immunity to the infection. The critical glycoprotein S of SARS-CoV-2 is responsible for virus binding and entry. The S precursor protein of SARS-CoV-2 can be proteolytically cleaved into S1 (685 aa) and S2 (588 aa) subunits. The S2 protein is well conserved among SARS-CoV-2 viruses and shares 99% identity with that of bat SARS-CoVs. The vaccine design based on the S2 protein may boost the broad-spectrum antiviral effect and is worth testing in animal models. Antibodies against the conserved stem region of influenza hemagglutinin have been found to exhibit broadly cross-reactive immunity, but are less potent in neutralizing influenza A virus. In contrast, the S1 subunit consists of the receptor-binding domain (RBD), which mediates virus entry into sensitive cells through the host angiotensin-converting enzyme 2 (ACE2) receptor.