The development of effective antiviral therapy for COVID-19 is critical for those awaiting vaccination, as well as for those who do not respond robustly to vaccination. This review summarizes 1 year of progress in the race to develop antiviral therapies for COVID-19, including research spanning preclinical and clinical drug development efforts, with an emphasis on antiviral compounds that are in clinical development or that are high priorities for clinical development. The review is divided into sections on compounds that inhibit SARS-CoV-2 enzymes, including its polymerase and proteases; compounds that inhibit virus entry, including monoclonal antibodies; interferons; and repurposed drugs that inhibit host processes required for SARS-CoV-2 replication. The review concludes with a summary of the lessons to be learned from SARS-CoV-2 drug development efforts and the challenges to continued progress.

SARS-CoV-2 Antiviral Therapy.

We summarize here in vitro evidences of efficacy for convalescent plasma, currently approved vaccines and monoclonal antibodies against SARS-CoV-2 variants of concern (VOC: B.1.1.7, B.1.351, P.1, and B.1.617.2), variants of interest (VOI: B.1.427/B.1.429, P.2, B.1.525, P.3, B.1.526, and B.1.671.1), and other strains (B.1.1.298 and B.1.258delta). While waiting from real world clinical efficacy, these data provide guidance for the treating physician.

SARS-CoV-2 Variants: A Synopsis of In Vitro Efficacy Data of Convalescent Plasma, Currently Marketed Vaccines, and Monoclonal Antibodies.

COVID‐19 convalescent plasma (CCP) was among the few frontline therapies used to treat COVID‐19. After large randomized controlled trials (RCTs) relying on late use in hospitalized patients and/or low antibody titres failed to meet their predefined primary endpoint, the infectious disease community reduced usage of CCP in favour of monoclonal antibodies. Consequently, there are CCP stocks at most transfusion centres worldwide, although scattered usage continues. Further, better designed RCTs are also being launched. The urgent question here is: should we use CCP units collected months before given the largely changed viral variant landscape? We review here in vitro evidence that discourages usage of such CCP units against Delta and other variants of concern. CCP collections should be continued in order to update the armamentarium of therapeutics against vaccine breakthrough infections or in unvaccinated patients and is especially relevant in next‐generation RCTs.

Are convalescent plasma stocks collected during former COVID‐19 waves still effective against current SARS‐CoV‐2 variants?

Background: Recently emerged SARS-CoV-2 variants may pose a threat to immunity derived from prototypical SARS-CoV-2 infection or vaccination. A systematic summary of the landscape of neutralizing antibodies against emerging variants is needed. 

Methods: We systematically searched PubMed, Embase, Web of Science, and 3 pre-print servers for studies that evaluated neutralizing antibodies titers induced by previous infection or vaccination against SARS-CoV-2 variants and comprehensively collected individual data. Through pooled analyses we estimated lineage-specific GMTs across different study participants and types of neutralization assays. 

Findings: We identified 76 studies, including 2,876 individuals and 10,526 neutralization tests, meeting the eligibility criteria. Compared with reference lineage B, B.1.351 and B.1.617 significantly escaped natural-infection-mediated neutralization, with an average of 3.8-fold (95% CI: 3.4-4.4) and 4.0-fold (95% CI: 2.3-6.9) reduction in live virus neutralization assay, while neutralizing antibody titers against B.1.1.7 decreased slightly (1.3-fold, 95%CI: 1.1-1.6). Serum from vaccinees also led to significant reductions in neutralization of B.1.351 and B.1.617, with a 32.6-fold (95% CI: 18.7-56.9) and 11.4-fold (95% CI: 8.6-15.2) for non-replicating vector vaccines, while 4.4-fold (95% CI: 4.0-5.0) and 2.1-fold (95%CI: 1.6-2.8) for mRNA platform vaccine. Neutralizing antibodies levels induced mRNA vaccines against SARS-CoV-2 variants were similar, or higher, than that derived from naturally-infected individuals. 

Interpretation: Antibody responses established by natural infection or vaccination have similar ability to neutralize B.1.1.7, but neutralizing titers against B.1.351 and B.1.617 were significantly reduced. Standardized protocols for neutralization assays, as well as updating immune-based prevention and treatment, are needed.

Registration Information: The study has been registered with PROSPERO and is awaiting approval (ID: 256932).

Funding Information: This study was funded by the National Science Fund for Distinguished Young Scholars (grant no. 81525023), Program of Shanghai Academic/Technology Research Leader (grant no.18XD1400300), National Science and Technology Major project of China (grant no. 2018ZX10713001-007, 2017ZX10103009-005, 2018ZX10201001-010), the US National Institutes of Health (R01 AI135115 to D.T.L. and A.S.A.)

Declaration of Interests: H.Y. has received research funding from Sanofi Pasteur, and Shanghai Roche Pharmaceutical Company; D.T.L. and A.S.A. has received research funding from the US National Institutes of Health. None of those research funding is related to COVID-19. All other authors report no competing interests.

Neutralizing Antibodies Against SARS-CoV-2 Variants Induced by Natural Infection or Vaccination: A Systematic Review and Individual Data Meta-Analysis

Background Although progressive COVID-19 vaccinations provide a significant reduction of infection rate in the short-to mid-term, effective COVID-19 treatments will continue to be an urgent need. Methods We have functionally characterized the anti-SARS-CoV-2 hyperimmune immunoglobulin (hIG) prepared from human COVID-19 convalescent plasma. SARS-CoV-2 virus neutralization was evaluated by four different methodologies (plaque reduction, virus induced cytotoxicity, TCID50 reduction and immunofluorimetry-based methodology) performed at four different laboratories and using four geographically different SARS-CoV-2 isolates (one each from USA and Italy; two from Spain). Two of the isolates contained the D614G mutation. Neutralization capacity against the original Wuhan SARS-CoV-2 straom and variants (D614G mutant, B.1.1.7, P.1 and B.1.351 variants) was evaluated using a pseudovirus platform expressing the corresponding spike (S) protein. The capacity to induce antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) was also evaluated. Results All the SARS-CoV-2 isolates tested were effectively neutralized by hIG solutions. This was confirmed by all four methodologies showing potent neutralization capacity. Wild-type SARS-CoV-2 and variants were effectively neutralized as demonstrated using the pseudovirus platform. The hIG solutions had the capacity to induce ADCC and ADCP against SARS-CoV-2 N and S proteins but not the E protein. Under our experimental conditions, very low concentrations (25-100 µg IgG/mL) were required to induce both effects. Besides the S protein, we observed a clear and potent effect triggered by antibodies in the hIG solutions against the SARS-CoV-2 N protein. Conclusions These results show that, beyond neutralization, other IgG Fc-dependent pathways may play a role in the protection from and/or resolution of SARS-CoV-2 infection when using hIG COVID-19 products. This could be especially relevant for the treatment of more neutralization resistant SARS-CoV-2 variants of concern.

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Anti-SARS-CoV-2 hyperimmune immunoglobulin provides potent and robust neutralization capacity and antibody-dependent cellular cytotoxicity and phagocytosis induction through N and S proteins

Hyperimmune immunoglobulin (hCoV-2IG) preparations generated from SARS-CoV-2 convalescent plasma (CP) are under evaluation in several clinical trials of hospitalized COVID-19 patients. Here we explored the antibody epitope repertoire, antibody binding and virus neutralizing capacity of six hCoV-2IG batches as well as nine convalescent plasma (CP) lots against SARS-CoV-2 and emerging variants of concern (VOC). The Gene-Fragment Phage display library spanning the SARS-CoV-2 spike demonstrated broad recognition of multiple antigenic sites spanning the entire spike including NTD, RBD, S1/S2 cleavage site, S2-fusion peptide and S2-heptad repeat regions. Antibody binding to the immunodominant epitopes was higher for hCoV-2IG than CP, with predominant binding to the fusion peptide. In the pseudovirus neutralization assay (PsVNA) and in the wild-type SARS-CoV-2 PRNT assay, hCoV-2IG lots showed higher titers against the WA-1 strain compared with CP. Neutralization of SARS-CoV-2 VOCs from around the globe were reduced to different levels by hCoV-2IG lots. The most significant loss of neutralizing activity was seen against the B.1.351 (9-fold) followed by P.1 (3.5-fold), with minimal loss of activity against the B.1.17 and B.1.429 ([≤]2-fold). Again, the CP showed more pronounced loss of cross-neutralization against the VOCs compared with hCoV-2IG. Significant reduction of hCoV-2IG binding was observed to the RBD-E484K followed by RBD-N501Y and minimal loss of binding to RBD-K417N compared with unmutated RBD. This study suggests that post-exposure treatment with hCoV-2IG is preferable to CP. In countries with co-circulating SARS-CoV-2 variants, identifying the infecting virus strain could inform optimal treatments, but would likely require administration of higher volumes or repeated infusions of hCOV-2IG or CP, in patients infected with the emerging SARS-CoV-2 variants.

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Huang C

Papers

Reduced neutralization of SARS-CoV-2 variants by convalescent plasma and hyperimmune intravenous immunoglobulins for treatment of COVID-19