Remdesivir, Molnupiravir, Nirmatrelvir remain active against Omicron, other variants of concern

 LauraVangeelaWinstonChiuaStevenDe JongheaPietMaesbBramSlechtencJorenRaymenantscdEmmanuelAndrécdPieterLeyssenaJohanNeytsa1DirkJochmansa

DOI: https://doi.org/10.1016/j.antiviral.2022.105252

PDF: https://www.sciencedirect.com/science/article/pii/S0166354222000201/pdfft?md5=1d6a05f462589a478c2c3cae742fff85&pid=1-s2.0-S0166354222000201-main.pdf

Highlights

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The omicron SARS-CoV-2 variant remains susceptible for GS-441524, Remdesivir, EIDD-1931, Molnupiravir and Nirmatrelvir.

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The target genes of these antivirals are highly conserved between SARS-CoV-2 variants.

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Similarly, the alpha, beta, gamma and delta variants remain susceptible to these antivirals.

Abstract

We assessed the in vitro antiviral activity of remdesivir and its parent nucleoside GS-441524, molnupiravir and its parent nucleoside EIDD-1931 and the viral protease inhibitor nirmatrelvir against the ancestral SARS-CoV2 strain and the five variants of concern including Omicron. VeroE6-GFP cells were pre-treated overnight with serial dilutions of the compounds before infection. The GFP signal was determined by high-content imaging on day 4 post-infection. All molecules have equipotent antiviral activity against the ancestral virus and the VOCs Alpha, Beta, Gamma, Delta and Omicron. These findings are in line with the observation that the target proteins of these antivirals (respectively the viral RNA dependent RNA polymerase and the viral main protease Mpro) are highly conserved.

https://www.sciencedirect.com/science/article/pii/S0166354222000201

Efficacy and Safety of a Plant-Based Virus-Like Particle Vaccine for COVID-19 Adjuvanted with AS03

 Karen Joyce Hager, Gonzalo Pérez Marc, Philipe Gobeil, Ricardo Sobhie Diaz, Gretchen Heizer, Conrado Llapur, Alexander I. Makarkov, Eduardo Vasconcellos, Stephane Pillet, Fernando Riera, Kapil Bhutada, Priscila Geller Wolff, Garry Wallace, Hessam Aazami, Christine E Jones, Fernando P. Polack, Judith Atkins, Iohann Boulay, Jiwanjeet Dhaliwall, Nathalie Charland, Manon Couture, Julia Jiang-Wright, Nathalie Landry, Sophie Lapointe, Aurélien Lorin, Asif Mahmood, Lawrence H Moulton, Emmy Pahmer, Julie Parent, Pooja Saxena, Annie Seguin, Luan Tran, Thomas Breuer, Maria Angeles Ceregido, Marguerite Koutsoukos, Francois Roman, Junya Namba, Marc-André D'Aoust, Sonia Trepanier, Yosuke Kimura, The CoVLP Study Team, Brian J Ward

doi: https://doi.org/10.1101/2022.01.17.22269242

This article is a preprint and has not been certified by peer review [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

PDF: https://www.medrxiv.org/content/10.1101/2022.01.17.22269242v1.full.pdf

Abstract

Background: Several COVID-19 vaccines are currently being deployed but supply constraints, concerns over durability of immune responses, solidifying vaccine hesitancy/resistance and vaccine efficacy in the face of emerging variants mean that new vaccines continue to be needed to fight the ongoing pandemic. The vaccine described here is an enveloped, coronavirus-like particle produced in plants (CoVLP) that displays the prefusion-stabilized spike (S) glycoprotein of SARS-CoV-2 (ancestral Wuhan strain) and is adjuvanted with AS03 (CoVLP+AS03). Methods: This Phase 3 randomized, observer-blind, placebo-controlled trial was conducted at 85 centers in Argentina, Brazil, Canada, Mexico, the UK, and the USA. Adults ≥18 years of age including those at high risk for COVID-19 complications were randomly assigned 1:1 to receive two intramuscular injections of CoVLP (3.75 μg) adjuvanted with AS03 or placebo, 21 days apart. The primary efficacy endpoint was prevention of symptomatic (≥ 1 symptom), PCR-confirmed SARS-CoV-2 infection with onset at least 7 days after the second injection and was triggered by the identification of ≥160 virologically-confirmed cases. Tolerability and safety of CoVLP+AS03 were also determined. Results: A total of 24,141 volunteers were randomly assigned 1:1 to receive vaccine or placebo (N= 12,074 and 12,067, respectively: median age 29, range 18 to 86 years). Overall, 83% received both doses. 14.8% were SARS-CoV-2 seropositive at baseline. Symptomatic SARS-CoV-2 infection was confirmed in 165 study participants in the intention to treat (ITT) set and 157 in the per-protocol population (PP) set. Of the 157 in the PP set, 118 COVID-19 cases were in the placebo group and 39 COVID-19 cases were in the CoVLP+AS03 group for an overall vaccine efficacy (VE) of 71.0% (95% confidence interval (CI) 58.6, 80.0). Moderate-to-severe COVID-19 occurred in 8 and 32 participants in the CoVLP+AS03 and placebo groups, respectively: VE 78.1% (95% CI: 53.9, 90.5) in the PP set overall and 84.5% (95% CI: 62.0, 94.7) in those seronegative at recruitment. To date, 100% of the sequenced strains (122/165 cases: 73.39%) were variants, dominated by Delta (45.9%) and Gamma (43.4%) strains. Vaccine efficacy by variant was 75.3% (95% CI 52.8, 87.9) against Delta and 88.6% (95% CI 74.6, 95.6) against Gamma. Cross-protection was also observed against Alpha, Lambda and Mu variants; although fewer cases were identified, all were in the placebo group. At diagnosis, viral loads in the CoVLP+AS03 breakthrough cases were >100-fold lower than in the placebo cases. Reactogenicity data for solicited adverse events (AEs) was analysed for a subset (N=4,136 in vaccine arm and N=3,683 for placebo) of participants. Reactogenicity was mostly mild to moderate, and transient, and occurred more frequently in the CoVLP+AS03 group. The safety analysis set used for unsolicited AE assessment comprised 24,076 participants who received at least one study injection: 12,036 received CoVLP+AS03 and 12,040 received placebo. All serious adverse events were assessed as unrelated, except two events reported in the same subject in the placebo group. No significant imbalance or safety concern was noted in medically attended AEs (MAAEs), adverse event of special interest (AESIs), AEs leading to withdrawal, deaths, or adverse events potentially associated with currently authorized vaccines. Conclusions: The CoVLP+AS03 vaccine candidate conferred an efficacy of 71.0% in preventing symptomatic SARS-CoV-2 infection caused by a spectrum of variants. Vaccine efficacy of 78.1% was observed against moderate and severe disease, while variant-specific efficacy ranged from 75.3% to 100%. Markedly lower viral loads in the CoVLP+AS03 group at the time of diagnosis suggests a significant virologic impact of vaccination even in the breakthrough cases. CoVLP+AS03 vaccine candidate was well tolerated, and no safety concerns were identified during the study. If approved by regulators, this more traditional protein+adjuvant vaccine produced using the novel plant-based platform may be able to make an important contribution to the global struggle against the increasingly complex family of SARS-CoV-2 viruses (Funded by Medicago with grants from the governments of Quebec and Canada; NCT04636697).

Competing Interest Statement

During the period of the study KJH, PG, GH, AIM, SP, KB, JA, IB, JD, NC, MC, JJW, NL, SL, AL, AM, EP, JP, PS, AS, LT, JN, MAD, ST, YK, BJW were either employees of Medicago Inc. or received salary support from Medicago Inc. TB, MAC, MK, FR are employed by the GlaxoSmithKline (GSK) group of companies and hold restricted shares in the group of companies. LHM received compensation from Medicago as a consultant.

Clinical Trial

NCT04636697

Clinical Protocols

https://clinicaltrials.gov/ct2/show/NCT04636697

Funding Statement

The study was sponsored by Medicago Inc.

https://www.medrxiv.org/content/10.1101/2022.01.17.22269242v1

Reinfections in COVID-19 Patients: Impact of Virus Genetic Variability and Host Immunity

 y 

Aisha Fakhroo

 ¹,

Hebah A. AlKhatib

 ²,

Asmaa A. Al Thani

 ² and

Hadi M. Yassine

 ^2,*

^DOI: https://doi.org/10.3390/vaccines9101168

PDF: https://www.mdpi.com/2076-393X/9/10/1168/pdf

Abstract

The COVID-19 pandemic is still posing a devastating threat to social life and economics. Despite the modest decrease in the number of cases during September–November 2020, the number of active cases is on the rise again. This increase was associated with the emergence and spread of the new SARS-CoV-2 variants of concern (VOCs), such as the U.K. (B1.1.7), South Africa (B1.351), Brazil (P1), and Indian (B1.617.2) strains. The rapid spread of these new variants has raised concerns about the multiple waves of infections and the effectiveness of available vaccines. In this review, we discuss SARS-CoV-2 reinfection rates in previously infected and vaccinated individuals in relation to humoral responses. Overall, a limited number of reinfection cases have been reported worldwide, suggesting long protective immunity. Most reinfected patients were asymptomatic during the second episode of infection. Reinfection was attributed to several viral and/or host factors, including (i) underlying immunological comorbidities; (ii) low antibody titers due to the primary infection or vaccination; (iii) rapid decline in antibody response after infection or vaccination; and (iv) reinfection with a different SARS-CoV-2 variant/lineage. Infections after vaccination were also reported on several occasions, but mostly associated with mild or no symptoms. Overall, findings suggest that infection- and vaccine-induced immunity would protect from severe illness, with the vaccine being effective against most VOCs.

https://www.mdpi.com/2076-393X/9/10/1168