Messenger RNA Vaccines Against COVID-19 and its Variants

The novel messenger RNA (mRNA) vaccines developed by Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273) carry the genetic code the host cell needs to make the surface spike protein antigen to closely mimic a natural infection.1

To study the effectiveness of these vaccines, the US Centers for Disease Control and Prevention (CDC) conducted a longitudinal real-world study evaluating BNT162b2 and mRNA-1273 in nearly 4,000 healthcare professionals and first responders. Interim results show reduced risk of infection by 80% after partial vaccination, which fell to 90% after the second dose.2 These findings are similar to later stage trials showing that two-dose regimens of BNT162b2 and mRNA-1273 provide approximately 95% protection against COVID-19.3,4

Trials of mRNA vaccines were mainly conducted in the United States before variants of concern had been detected. Variants of concern are strains of SARS-CoV-2 that show evidence of increased transmissibility and/or disease severity and reduced effectiveness against therapies developed for prevention and treatment.5 These include the emergence of variants first identified in the United Kingdom (B.1.1.7, B.1.1.7+E48K), South Africa (B.1.351), Brazil (P.1), and California (B.1.427, B.1.429).
Much of the data of mRNA vaccine efficacy against new strains of the virus comes from laboratory models of SARS-CoV-2 variants. Serum samples from people immunized with BNT162b2 were exposed to genetically engineered versions of variants: B.1.1.7-spike, P.1-spike, and B.1.351-spike.6,7 This study showed approximately equivalent neutralizing antibodies of B.1.1.7-spike and P.1-spike, and robust but lower levels of neutralizing antibodies against B.1.351-spike.7

Serum samples of people who received mRNA-1273 were assayed against a recombinant vesicular stomatitis virus (rVSV)-based SARS-CoV-2 model of pseudoviruses carrying the strains B.1.1.7, B.1.351, P.1, B.1.427, B.1.429, B.1.1.7+E484K, and other variants.8 The study showed no significant effect on neutralization of B.1.1.7, but a decrease in titers of neutralizing antibodies against P.1, B.1.427, B.1.429, B.1.1.7+E484K, and B.1.351 variants.8

References
 

  1. Abbasi J. COVID-19 and mRNA vaccines—first large test for a new approach. JAMA. 2020;324(12):1125-1127.
  2. Thompson MG, Burgess JL, Naleway AL, et al. Interim estimates of vaccine effectiveness of BNT162b2 and mRNA-1273 COVID-19 vaccines in preventing SARS-CoV-2 infection among health care personnel, first responders, and other essential and frontline workers — Eight U.S. Locations, December 2020-March 2021. MMWR Morb Mortal Wkly Rep. ePub: 29 March 2021.
  3. Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med. 2020;383:2603-2615.
  4. Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med. 2021;384:403-416. 5. CDC. SARS-CoV-2 Variant Classifications and Definitions. Available at https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-surveillance/variant-info.html. Accessed March 31, 2021.
  5. Rubin R. COVID-19 vaccines vs variants—determining how much immunity is enough. JAMA. Published online March 17, 2021. Accessed March 30, 2021.
  6. Liu Y, Liu J, Xia H, et al. Neutralizing activity of BNT162b2-elicited serum. N Engl J Med. March 8, 2021. DOI: 10.1056/NEJMc2102017
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Updates in the Treatment and Prevention of COVID-19​

Subcutaneous Administration of Casirivimab and Imdevimab Reduced the Risk of Symptomatic COVID-19 by 81% Among Household Contacts

Top-line results from a phase 3 trial showed that the combination of casirivimab and imdevimab reduced the risk of symptomatic infections by 81% among household contacts of SARS-CoV-2 infected individuals. The trial enrolled 1,505 individuals who did not have COVID-19 symptoms or anti-SARS-CoV-2 antibodies, but who lived in the same household as an individual who tested positive for SARS-CoV-2 within the prior 4 days. A single subcutaneous injection of casirivimab and imdevimab provided rapid protection to those with exposure to SARS-CoV-2 at home, with protection against symptomatic infections ranging from 72% in the first week to 93% in subsequent weeks. Individuals who developed symptomatic infections despite casirivimab and imdevimab therapy had a shorter duration of symptoms compared with those who received placebo (1 week vs 3 weeks, respectively). Infected individuals who received therapy also cleared the virus faster. Adverse events (AEs) occurred in 20% of patients receiving casirivimab and imdevimab and 29% of patients receiving placebo. Injection site reactions, all of which were grades 1-2, occurred in 4% of patients in the treatment group and 2% of placebo participants.

Casirivimab and Imdevimab Significantly Reduced Progression to Symptomatic COVID-19 in Recently Infected Asymptomatic Patients

In a phase 3 trial of 204 recently infected asymptomatic COVID-19 patients, subcutaneous administration of casirivimab and imdevimab reduced the overall risk of progressing to symptomatic COVID-19 by 31%, and by 76% after the third day. In addition to reducing the risk of symptomatic infections, the top-line results report that the combination of casirivimab and imdevimab shortened the total number of weeks patients experienced symptoms by 45% and reduced the viral burden by more than 90%. No patients withdrew from the trial due to AEs in either group. Casirivimab and imdevimab are investigational drugs with emergency use authorization for the treatment of individuals with mild-to-moderate COVID-19 who are at high-risk of progressing to severe COVID-19 or hospitalization. Casirivimab and imdevimab (REGEN-COV™) continues to be evaluated in clinical trials in multiple settings for COVID-19, including the open-label RECOVERY trial of hospitalized patients in the UK.

Johnson & Johnson COVID-19 Vaccine Administration Paused

The Centers for Disease Control and Prevention (CDC) and the Federal Drug Administration (FDA) are recommending a pause in the use of the Ad26.COV2.S vaccine developed by Johnson & Johnson (Janssen) as they review data involving 6 reported cases of a rare and severe type of blood clot in individuals after vaccination. The vaccine has been administered to more than 6.8 million individuals in the US. In all 6 reported cases, a type of blood clot called cerebral venous sinus thrombosis (CVST) occurred in combination with low platelet levels (thrombocytopenia). Treatment of CVST differs from other blood clots and administration of heparin may be dangerous in these patients. All 6 cases occurred among women aged 18 to 48 years and symptoms usually occurred 6 to 13 days after vaccination. People who develop severe headache, abdominal pain, leg pain, or shortness of breath within 3 weeks after vaccination should contact their healthcare provider.

References:

Regeneron Press Release. Phase 3 Prevention Trial Showed 81% Reduced Risk of Symptomatic SARS-CoV-2 Infections with Subcutaneous Administration of REGEN-COV™ (Casirivimab and Imdevimab). April 12, 2021. Available at: https://investor.regeneron.com/news-releases/news-release-details/phase-3-prevention-trial-showed-81-reduced-risk-symptomatic-sars

Regeneron Press Release. Phase 3 Treatment Trial in Recently Infected Asymptomatic Patients Showed REGEN-COV™ (Casirivimab and Imdevimab) Significantly Reduced Progression to Symptomatic COVID-19. April 12, 2021. Available at: https://investor.regeneron.com/news-releases/news-release-details/phase-3-treatment-trial-recently-infected-asymptomatic-patients

FDA Statement. Joint CDC and FDA Statement on Johnson & Johnson COVID-19 Vaccine. April 13, 2021. Available at: https://www.fda.gov/news-events/press-announcements/joint-cdc-and-fda-statement-johnson-johnson-covid-19-vaccine