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An mRNA Vaccine Against SARS-CoV-2
TAKE-HOME MESSAGE
- This phase I dose-escalation trial evaluated a novel mRNA vaccine against SARS-CoV-2 at three different dose levels among a total of 45 healthy adults.
- An immune response was registered in all participants, with binding and neutralizing antibody titers induced by a two-dose schedule similar to those found in convalescent serum specimens. No trial-limiting safety concerns were identified.
– Neil Majithia, MD
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and spread globally, prompting an international effort to accelerate development of a vaccine. The candidate vaccine mRNA-1273 encodes the stabilized prefusion SARS-CoV-2 spike protein.
METHODS
We conducted a phase 1, dose-escalation, open-label trial including 45 healthy adults, 18 to 55 years of age, who received two vaccinations, 28 days apart, with mRNA-1273 in a dose of 25 μg, 100 μg, or 250 μg. There were 15 participants in each dose group.
RESULTS
After the first vaccination, antibody responses were higher with higher dose (day 29 enzyme-linked immunosorbent assay anti-S-2P antibody geometric mean titer [GMT], 40,227 in the 25-μg group, 109,209 in the 100-μg group, and 213,526 in the 250-μg group). After the second vaccination, the titers increased (day 57 GMT, 299,751, 782,719, and 1,192,154, respectively). After the second vaccination, serum-neutralizing activity was detected by two methods in all participants evaluated, with values generally similar to those in the upper half of the distribution of a panel of control convalescent serum specimens. Solicited adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Systemic adverse events were more common after the second vaccination, particularly with the highest dose, and three participants (21%) in the 250-μg dose group reported one or more severe adverse events.
CONCLUSIONS
The mRNA-1273 vaccine induced anti-SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified. These findings support further development of this vaccine.
Additional Info
Disclosure statements are available on the authors' profiles:
An mRNA Vaccine Against SARS-CoV-2 — Preliminary Report
N. Engl. J. Med 2020 Jul 14;[EPub Ahead of Print], LA Jackson, EJ Anderson, NG Rouphael, PC Roberts, M Makhene, RN Coler, MP McCullough, JD Chappell, MR Denison, LJ Stevens, AJ Pruijssers, A McDermott, B Flach, NA Doria-Rose, KS Corbett, KM Morabito, S O'Dell, SD Schmidt, PA Swanson, M Padilla, JR Mascola, KM Neuzil, H Bennett, W Sun, E Peters, M Makowski, J Albert, K Cross, W Buchanan, R Pikaart-Tautges, JE Ledgerwood, BS Graham, JH BeigelFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Emerging Vaccines for SARS-CoV-2
What do a replication-deficient chimpanzee adenovirus, a replication-defective human type-5 adenovirus, and a lipid nanoparticle have in common? When talking about prototype COVID-19 vaccines, they all contain the RNA that codes for the spike glycoprotein necessary for SARS-CoV-2 binding with, and entry into, human cells. In addition, all three of these vaccines have now passed important waypoints along the pathway to licensure, recommendation, and widespread use. In many other ways, however, they are extremely different.
A chimpanzee adenovirus (ChAd) candidate vaccine emerged in response to the Middle East respiratory syndrome (MERS) coronavirus. Using a similar approach, a new vaccine (ChAdOx1) employs the replication-deficient ChAd as a vector containing the RNA sequence for the spike protein. In a phase I/II randomized controlled trial (RCT) involving 1077 participants, Folegatti and colleagues demonstrated peak T-cell response 14 days after immunization, rising anti-spike antibody at day 28, and neutralizing antibody responses in 91% to 100% of subjects for whom these assays were performed.1 Although local and systemic reactions were common and included pain, feverishness, chills, myalgia, headache, and malaise, no serious adverse events occurred.
Researchers in China have created a vaccine using a replication-defective type-5 human adenovirus as a vector of the full-length spike protein gene. This vaccine—in two dosing strengths—or a placebo were administered to 508 participants in a phase II RCT in Wuhan, China.2 Seroconversion rates for receptor binding domain antibodies were 96% to 97% depending on dose at day 28. In addition, both dosages produced neutralizing antibody to live SARS-CoV-2. Again, local and systemic reactions (pain, fever, headache, and fatigue) were common, and severe adverse events were noted in 9% of the higher-dose recipients. No serious side effects were reported.
We currently do not have any mRNA vaccines in our armamentarium against infectious diseases. A COVID-19 candidate, co-developed by the National Institute of Allergy and Infectious Diseases and Moderna, is a “lipid nanopartical-encapsulated, nucleoside-modified mRNA-based vaccine.”3 This vaccine was recently assessed in a phase I trial involving 45 participants who received two doses, 28 days apart. Three different doses (25 µg, 100 µg, 250 µg) were used. The higher doses produced higher anti-spike antibody on day 29, and all levels were increased following the booster dose. Serum-neutralizing activity, measured after the second dose was comparable to that of convalescent serum. Vaccine side effects were common and included fatigue, chills, headache, myalgia, and injection site pain.
Taken together, these studies demonstrate that early endpoints for new vaccine development are being met: the novel candidates are producing measurable antibody in most vaccine recipients which is able to neutralized SARS-CoV-2. They are achieving this seroconversion without notable serious adverse effects, although local and systemic effects are common. The challenge now comes in terms of these candidates’ ability to prevent SARS-CoV-2 infection/transmission and reduce the illnesses, hospitalizations, intensive care requirements, and deaths attributable to COVID-19, and in the durability of the imparted immune response. That is the role of phase III trials that are now underway and longitudinal monitoring. Such trials require large numbers of participants and sufficient time for exposure to, and acquisition of, SARS-CoV-2 infection, allowing for estimates of effectiveness and better ascertainment of safety.
References