US biotechnology firm Moderna on Monday said lab studies showed its COVID-19 vaccine remains effective against variants of the coronavirus first identified in the United Kingdom and South Africa.
But the positive news was tempered by the finding that there was a sixfold reduction in the level of highly-potent neutralizing antibodies produced against the South African variant, B.1.351.
Out of caution, the company will test adding a second booster of its vaccine—to make three shots in total—and has begun preclinical studies on a booster specifically for the South African variant.
“We are encouraged by these new data, which reinforce our confidence that the Moderna COVID-19 Vaccine should be protective against these newly detected variants,” said Stephane Bancel, Moderna’s CEO.
“Out of an abundance of caution and leveraging the flexibility of our mRNA platform, we are advancing an emerging variant booster candidate against the variant first identified in the Republic of South Africa into the clinic.”
Akiko Iwasaki, a leading virologist from Yale, tweeted: “This is good,” adding that she expected other vaccine makers were also developing boosters that target the South African variant.
But Lawrence Young, a virologist at Britain’s Warwick University, said the sixfold reduction was a matter “of concern” and suggested vaccine efficacy as well as duration of protection could be impacted.
He added it was difficult to read too much into data that had been presented from a limited number of samples and only thus far as a press release, not a scientific paper.
The emergence of highly contagious variants to the SARS-CoV-2 virus had triggered concern about their impact on the efficacy of COVID-19 vaccines even as countries begin to accelerate their immunization programs.
Both the B.1.1.7 variant first seen in the UK and the B.1.351 variant have multiple mutations along the “spike protein,” molecules that dot the surface of the virus and allow it to invade human cells.
Scientists have been particularly worried that the mutations on B.1.351 would lead to the virus escaping the action of antibodies, and render the current generation of vaccines obsolete.
Moderna’s vaccine uses mRNA – a type of genetic molecule – to deliver the information for human cells to create the spike protein inside the human body, in order to trigger an immune response.
A booster for B.1.351 would therefore carry the mRNA that creates the spike protein with the mutations that are specific to the variant.
A major advantage of mRNA vaccines is that they can be developed in a matter of weeks, even though producing them to mass scale may take much longer.
The global vaccine race took another hit Monday as Merck announced it was halting work on two COVID-19 shots, including one being developed with France’s Pasteur Institute, after they found the immune response was inferior to other vaccines.
Scientific paper awaited
To study the impact of the Moderna vaccine, called mRNA-1273, the company took blood samples from eight people who had received two doses of the vaccine, and from primates that had also been immunized.
For the B.1.1.7 variant there was no impact on the level of neutralizing antibodies—which bind to the spike protein and prevent it from invading human cells – that were produced by the shots.
But for the South African variant, B.1.351, there was a sixfold reduction in the neutralizing antibody level.
Even so, the company said it remained above the quantity that was shown to be protective in earlier tests on primates that were infected on purpose.
Moderna, which carried out the studies with the National Institutes of Health, has submitted the study to a preprint server so it can be analyzed by the wider scientific community.
On November 30, 2020, ModernaTX (the Sponsor) submitted an Emergency Use Authorization (EUA) request to FDA for an investigational COVID-19 vaccine (mRNA-1273) intended to prevent COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The vaccine is based on the SARS-CoV-2 spike glycoprotein (S) antigen encoded by RNA and formulated in lipid nanoparticles (LNPs).
The proposed use under an EUA is for active immunization for the prevention of COVID-19 caused by SARS-CoV-2 in individuals 18 years of age and older. The proposed dosing regimen is 2 doses, 100 μg each, administered 1 month apart.
The EUA request includes safety and efficacy data from an ongoing Phase 3 randomized, double-blinded and placebo-controlled trial of mRNA-1273 in approximately 30,400 participants. The primary efficacy endpoint is the reduction of incidence of COVID-19 among participants without evidence of SARS-CoV-2 infection before the first dose of vaccine in the period after 14 days post-dose 2.
In an interim analysis conducted using a data cutoff of November 7, 2020, a total of 27,817 participants randomized 1:1 to vaccine or placebo with a median 7 weeks of follow-up post-dose 2 were included in the per-protocol efficacy analysis population of participants without evidence of SARS-CoV-2 infection prior to vaccination.
Efficacy in preventing confirmed COVID-19 occurring at least 14 days after the second dose of vaccine was 94.5.0% (95% CI 86.5%, 97.8%) with 5 COVID-19 cases in the vaccine group and 90 COVID-19 cases in the placebo group. Subgroup analyses of the primary efficacy endpoint showed similar efficacy point estimates across age groups, genders, racial and ethnic groups, and participants with medical comorbidities associated with high risk of severe COVID-19.
Secondary efficacy analyses suggested benefit of the vaccine in preventing severe COVID-19 (11 protocol-defined severe COVID-19 cases in the placebo group vs. 0 cases in the vaccine group), in preventing COVID-19 following the first dose, and in preventing COVID-19 in individuals with prior SARS-CoV-2 infection, although available data for some of these outcomes did not allow for firm conclusions.
Efficacy data from the final scheduled analysis of the primary efficacy endpoint (data cutoff of November 21, 2020, with a median follow-up of >2 months post-dose 2) demonstrated a VE of 94.1% (95% CI 89.3%, 96.8%), with 11 COVID-19 cases in the vaccine group and 185 COVID-19 cases in the placebo group and was consistent with results obtained from the interim analysis.
The VE in this analysis when stratified by age group was 95.6% (95% CI: 90.6%, 97.9%) for participants 18 to <65 years of age and 86.4% (95% CI: 61.4%, 95.5%) for participants ≥65 years of age. A final secondary efficacy analysis also supported efficacy against protocol-defined severe COVID-19, with 30 cases in the placebo group vs. 0 cases in the vaccine group.
Safety data from a November 11, 2020 interim analysis of approximately 30,350 participants
≥18 years of age randomized 1:1 to vaccine or placebo with a median of 7 weeks of follow-up after the second dose supported a favorable safety profile, with no specific safety concerns identified that would preclude issuance of an EUA. These safety data are the primary basis of FDA’s safety review. On December 7, 2020, the Sponsor submitted additional follow-up data from these participants with a cutoff of November 25, 2020, which represents a median of 9 weeks (>2 months) of follow-up post-dose 2. Key safety data from this later submission, including death, other serious adverse events, and unsolicited adverse events of interest were independently verified and confirmed not to change the safety conclusions from the interim safety analysis.
The most common solicited adverse reactions associated with mRNA-1273 were injection site pain (91.6%), fatigue (68.5%), headache (63.0%), muscle pain (59.6%), joint pain (44.8%), and
chills (43.4%); severe adverse reactions occurred in 0.2% to 9.7% of participants, were more frequent after dose 2 than after dose 1, and were generally less frequent in participants ≥65 years of age as compared to younger participants. Among unsolicited adverse events of clinical interest, which could be possibly related to vaccine, using the November 25, 2020 data cutoff, lymphadenopathy was reported as an unsolicited event in 173 participants (1.1%) in the vaccine group and 95 participants (0.63%) in the placebo group. Lymphadenopathy (axillary swelling and tenderness of the vaccination arm) was a solicited adverse reaction observed after any dose in 21.4% of vaccine recipients <65 years of age and in 12.4% of vaccine recipients ≥65 years of age, as compared with 7.5% and 5.8% of placebo recipients in those age groups, respectively.
There was a numerical imbalance in hypersensitivity adverse events across study groups, with 1.5% of vaccine recipients and 1.1% of placebo recipients reporting such events in the safety population. There were no anaphylactic or severe hypersensitivity reactions with close temporal relation to the vaccine.
Throughout the safety follow-up period to date, there were three reports of facial paralysis (Bell’s palsy) in the vaccine group and one in the placebo group. Currently available information is insufficient to determine a causal relationship with the vaccine. There were no other notable patterns or numerical imbalances between treatment groups for specific categories of adverse events (including other neurologic, neuro- inflammatory, and thrombotic events) that would suggest a causal relationship to mRNA-1273.
The frequency of serious adverse events was low (1.0% in the mRNA-1273 arm and 1.0% in the placebo arm), without meaningful imbalances between study arms. The most common SAEs in the vaccine group which were numerically higher than the placebo group were myocardial infarction (0.03%), cholecystitis (0.02%), and nephrolithiasis (0.02%), although the small numbers of cases of these events do not suggest a causal relationship. The most common SAEs in the placebo arm which were numerically higher than the vaccine arm, aside from COVID-19 (0.1%), were pneumonia (0.05%) and pulmonary embolism (0.03%).
With the exception of more frequent, generally mild to moderate reactogenicity in participants
<65 years of age, the safety profile of mRNA-1273 was generally similar across age groups, genders, ethnic and racial groups, participants with or without medical comorbidities, and participants with or without evidence of prior SARS-CoV-2 infection at enrollment.
This meeting of the Vaccines and Related Biological Products Advisory Committee (VRBPAC) is being convened to discuss and provide recommendations on whether, based on the totality of scientific evidence available, the benefits of the mRNA-1273 COVID-19 Vaccine outweigh its risks for use in individuals 18 years of age and older. The committee will also discuss what additional studies should be conducted by the vaccine manufacturer following issuance of the EUA to gather further data on the safety and effectiveness of this vaccine.