Antigen detection, antibodies, vaccines and drugs: multiple battlefields against novel coronavirus

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For people infected with novel coronavirus, rapid and accurate serological screening is very important for large-scale epidemiological evaluation and intervention. The prevalence rate in Slovakia is relatively high (about 3.9%), large-scale rapid detection of novel coronavirus in this country can identify many asymptomatic infected people, and prevent further community transmission through timely isolation. With the decrease of the prevalence of novel coronavirus, the proportion of false positives increases and the number of false negatives decreases. For example, in the case of 99.9% specificity and 80% sensitivity, the positive predictive value is 89% when the prevalence is 1%, while in the case of 0.1% prevalence, the positive predictive value decreases to 44%, that is, 55 out of 100 positive test results are false positive (1). Based on this situation, the UK also has emphasized the necessity of confirmatory RT-PCR after LFD rapid virus detection. In different areas, because of the different stages of the population prevalence, epidemiological curve, the mutation of the virus itself and the composition of different mutations in the infected population, and the complex hybrid stage brought by the blockade and reopening of society, the coordination of large-scale rapid detection and epidemic prevention system is still very important.

The molecular composition and antigen binding epitopes of circulating IgG antibodies in plasma after SARS-CoV-2 infection are still unclear. William N. Voss et al. (1) found that more than 80% of the antibody epitopes recognized outside the RBD (Receptor Binding Domain) region of Spike protein of novel coronavirus, and the appearance of NTD (N-terminal domain) targeted antibody and non-RBD-binding antibody played an important role in explaining the immune escape caused by mutant virus and new humoral immune mechanism (2).

In terms of drug development, a large number of studies on viral genome have found the core functional protein MPRO protein. Gunther et al. screened 37 compounds through X-ray crystallography, which could bind to the active site and two inactive allosteric sites of MPRO protein. Cytotoxicity test further verified that 7 of them have no obvious toxicity, and calcium peptide may have the highest antiviral activity (EC₅₀ = 72 nm, CC₅₀ > 100 μM). In other studies, calcium peptide could inhibit thrombin L, and this dual targeting effect on thrombin and SARS-CoV-2 virus functional protein MPRO made calcium peptide attractive (3). Since March 2020, the World Health Organization (WHO) has tested remdesivir, interferon, hydroxychloroquine, lopinavir-ritonavir, etc, with disappointing results. The RECOVERY study and REMAP-CAP study in June 2020 respectively proved that dexamethasone and interleukin-6 receptor antagonist could reduce the mortality of severe patients with novel coronavirus, suggesting the importance of blocking the immune response. TNF-α blockers, GM-CSF monoclonal antibodies (nanolumab), imatinib, artesunate and other drugs that can inhibit cytokine related inflammatory response are also in clinical research (4).

The main mutations of SARS-CoV-2 are amino acid substitutions (K417N, E484K and N501Y) in the RBD domain of Spike protein and amino acid substitutions or deletions in the N-terminal domain (NTD). A series of recent studies have shown that these mutations can lead to neutralizing antibody resistance and decreased vaccine efficacy (5-7). On the other hand, BNT162B2, a mRNA vaccine against SARS-CoV-2 jointly developed by Pfizer and BioNTech, continues to show strong effect. At the moment when Qatar was hit by the second round of novel coronavirus, Qatar would carry out a nationwide epidemic prevention operation since December 21, 2020. As of March 21, 2021, 385, 853 people have received at least one dose of the vaccine, and 265, 410 people have completed two doses of the vaccine. This wave of infection in Qatar was mainly caused by two variants, B.1.1.7 (44.5%) and B.1.351 (50%). About 2 weeks after the second vaccination with BNT162B2, the estimated effective rate of B.1.1.7 variant was 89.5% (95% confidence interval [CI], 85.9-92.3), and the estimated effective rate of B.1.351 variant was 75% (95% confidence interval [CI], 70.5-78.9). The efficacy of severe, critical or fatal virus was 97.4% (95% confidence interval [CI], 92.2-99.5) (8). This important data shows the importance of two doses of vaccine for variants (9). The research on the mutant and vaccine of novel coronavirus will become the most concerned direction in the next stage. The monoclonal antibodies COV2-2676 and COV2-2489 against NTD show some protective effects in animal models (10). Using CRISPR whole genome scanning method to study the interaction between SARS-CoV-2 RNA and host alveolar epithelial cells, ciliated cells and other intracellular proteins is helpful to find new drug targets (11-12).

References:

1, Garcia-Finana M, et al. Science. 2021;372:571-572.

2, Voss WN, et al. Science. 2021;eabg5268.

3, Gunther S, et al. Science. 2021;372:642-646.

4, Heidi Ledford. Nature. 2021 May 7.

5, Collier DA, et al. Nature. 2021;593:136-141.

6, Cele S, et al. Nature. 2021;593:142-146.

7, Wang PF, et al. Nature. 2021;593:130-135.

8, Abu-Raddad LJ & Butt AA. N Eng J Med. 2021 May 6.

9, Callaway E. Nature. 2021 May 6.

10, Suryadevara N. Cell. 2021;184:2316-2331.

11, Flynn RA, et al. Cell. 2021;184:2394-2411.

12, LeBlanc EV & Colpitts CC. Cell. 2021;184:2276-2278.