COVID: Moderna mRNA vaccine review

 The FDA released the Moderna coronavirus vaccine briefing document, see https://www.fda.gov/media/144434/download , (the peer-reviewed journal article has not been released yet, though I usually wait for the formal article prior to analysis. Of note, “the FDA has not independently verified the complete efficacy data from this dataset, beyond those analyses presented”, similarly for the safety dataset). This is a long blog, since I’ve gone through a lot of details from this (much longer) 54-page report

 

Details: 

-- 15,210 patients were randomized to vaccine versus placebo, as a two-dose regimen 28 days apart, in adults at least 18 years old from 99 sites in the United States 

    -- patients were stratified by age and health risk 

-- 47% female; mean age 52, 25% (3527) at least 65 years old; 79% white/10% Black/5% Asian/20% Latinx; occupational risk: 82% high-risk (healthcare workers, emergency workers, service workers, of which 25% healthcare workers) 

-- high risk condition: none in 78%, one in 22%, at least 2 in 4% 

    -- chronic lung disease, moderate to severe asthma, heart failure, coronary disease, congenital heart disease, cardiomyopathy, hypertension, morbid obesity, diabetes, liver disease, HIV 

-- health risk for severe Covid: 18-65-year-old: 

    -- 74% not at risk, 26% at risk 

    -- risk factors: chronic lung disease 5%, significant cardiac disease 5%, morbid obesity 7%, diabetes 9%, liver disease and HIV <1% 

-- exclusion criteria: under age 18, pregnancy; and not being actively ill, severely immunosuppressed

-- those who developed symptoms consistent with Covid prompted an unscheduled visit and nasopharyngeal swabbing for PCR 

 

-- 100% of patients received at least one dose of vaccine or placebo, two doses in 92% for both groups 

-- median follow-up was 50 days 

 

-- primary efficacy endpoints: efficacy of infection at least 14 days after the second dose in participants with a negative SARS-CoV-2 status at baseline, on a per-protocol basis (i.e. those receiving both shots on schedule) 

    -- case definition: symptomatic patients with positive PCR for SARS-CoV-2 and at least two of: fever, chills, myalgia, headache, sore throat, new olfactory/taste disorders; or at least one of: cough, shortness of breath or difficulty breathing, or clinical/radiologic evidence of pneumonia 

-- secondary efficacy endpoints:  

    -- severe Covid-19, death due to Covid-19, Covid-19 occurring at least 14 days after the first dose of vaccine 

    -- same as primary endpoint, but independent of prior history of SARS-CoV-2 infection 

 

-- mean follow-up 7 weeks after the second dose (adverse events will continue to be followed for 24 months) 

 

Results: 

--primary efficacy endpoint, beginning 14 days after the second-dose, in per-protocol setting (the final adjudicated committee assessment numbers were not significantly different from those below) 

    --all participants: vaccine 5 people infected (<0.1%), placebo 90 people (0.6%): vaccine efficacy 94.5% (86.5-97.8%) 

         --Incidence rate/1,000 person-yrs: 1.840 v s 33.365 

    --18 to <65yo: 5 people infected/10,407 vaccinated (<0.1%), vs 75 people infected/10,384 on placebo (0.7%): vaccine efficacy 93.4% (83.7-97.3%) 

         --Incidence rate/1,000 person-yrs: 2.504 v s 37.788 

    -- >65yo: vaccine 0 infected/3527 vaccinated, placebo 15 infected/3499 (0.4%): vaccine efficacy 100% 

         --Incidence rate/1,000 person-yrs: 0 v s 21.046 

    --cumulative Covid incidence: curves begin to separate around 14 days and reach statistically significant separation at 20 days after randomization (see their figure 2 on page 28) 

 

--subgroup analyses, comparing vaccine efficacy vs placebo: 

    --Age: 

        -- 18-65yo: see above 

        -- 65-74: 0/2904 vs 12/2823 infections (0.4%):  100% 

        -- at least 75yo: 0/623 vs 3/676 infections (0.4%): 100%  [pretty small numbers in this group] 

    --sex: 

        --female: 3/6661 vs 45/6514 infections: vaccine efficacy 93.0% (79.2-98.0%) 

        --male: 2/7273 vs 45/7369 infections: 95.5% (81.5-98.9%) 

    --race/ethnicity: 

        --non-Hispanic white: 5/8858 vs 70/8755: 93.0% (82.6-97.2%) 

        --communities of color: 0/5054 vs 20/5102: 100% 

        --Latinx: 0/2783 vs 12/2769: 100% 

    --Age and risk for severe covid: 

        --18-64yo and not at risk: 4/8309 vs 57/8323: 93.0% (80.8-97.5%) 

        --18-64yo and at risk: 1/2098 vs 18/2061: 94.6%  (59.4-99.3%) 

         --at least 65yo: 0/3527 vs 15/3499 (this was the total, no further stratification) 

--for patients with prior positive Covid-19 status: 

        --positive : 0/341 vs 1/334 case (0.3%) [also small numbers]

        --negative: 6/14,312 vs 90/14,370: 93.4% effective (84.8-97.1%) 

--by underlying condition: 

    --chronic lung disease: 0/661 vs 6/673, 100% effective 

    --significant cardiac disease: 0/686 vs 6/673 (0.9%), 100% 

    --BMI >40: 1/901 vs 11/884 (1.2%), 91.2% (32.0-98.9%) 

    --BMI >30: 2/5269 vs 46/5207 (0.9%): 95.8% (82.6-99.0%) 

    --diabetes: 0/1338 vs 7/1309 (0.5%): 100% 

    --liver disease: 0/93 vs 0/90 

    --HIV: 0/80 vs 1/76 

--severe Covid cases: 0/13934 vs 11/13883: 100% effective  [though very small numbers with severe Covid in the placebo group, ??reflecting the healthy cohort studied??]

 

--vaccine efficacy after first dose, overall 7/996 vs 39/1079 infections: 80.2% (55.2-92.5%) 

    --in first 14 days after the dose: 5/996 vs 11/1079: 50.8% (-53.6 to 86.6%) [ie vaccine did not show efficacy prior to the expected time it would take to work] 

    -- >14 days after the first dose: 2/983 vs 28/1050 : 92.1% (68.8-99.1%) 

     

safety: 

-- at least one adverse event: 14,338/15,176 (94.5%) in the vaccine group, versus 9027/15,162 (59.5%) in the placebo group (these were solicited adverse reactions, unsolicited were 21.9% versus 19.4%)  

-- local adverse reaction: 13,962/15,176 (92.0%) vaccine group, versus 4381/15,161 (28.9%) placebo  

-- grade 3 adverse reaction 1386/15,176 (9.1%) versus 143/15,161 (0.9%) 

-- systemic adverse reaction: 12,553/15,176 (82.7%) versus 8032/15,162 (53%) 

-- grade 3 or 4 systemic adverse reactions 2501/15,176 (16.5%) versus 560/15,162 (3.7%) 

 

-- those adverse events felt to be related to the vaccine itself by the investigators (overall not much difference between those who were baseline SARS-CoV-2 positive versus negative; and in those greater than 65 years old for both the solicited and unsolicited adverse events, though older people had marginally lower adverse event rates): 

    -- unsolicited adverse events: 7.4% versus 4.0% 

    -- grade 3 unsolicited adverse events:  0.5% versus 0.2%  

    -- medically-attended adverse events: 0.8% versus 0.5% 

    -- serious adverse events:  both <0.1% 

    -- deaths: zero in both  

    -- adverse events leading to discontinuation of vaccine: 41 of 15,184 versus 71 of 15,165  

-- overall, the vast majority of adverse reactions were local and there was not much difference between reaction after dose one versus dose two.  

-- by far the largest adverse reaction was pain, in about 90% vaccine group and 19% in the placebo group . The median duration of pain was 2 to 3 days after the injections 

-- the largest systemic adverse reaction was fever, with fevers in about 35% overall lasting for two days after either vaccine injection, and with <0.1% having fever >104°F 

-- axillary lymphadenopathy was more common in those 18 to 64yo at 10.2% versus 4.8% of vaccine recipients after dose one, and 14 .0% versus 3.9% after dose 2.  And, for grade 3 axillary lymphadenopathy, 0.3% versus 0.2% after dose one and 0. 5% versus 0.1% after dose two 

-- systemic reactions persisting longer than seven days report in 11.9% with the vaccine and 9.5% with placebo; fever persisting that long was extremely rare: seven vaccine recipients and 4 placebo recipients 

-- other common reactions: headache in 85.4% versus 29% placebo, fatigue in 38.5% versus 28.8% with placebo, myalgias 23.7% versus 14.3% in placebo, arthralgias 16.6% versus 11.6% in placebo, nausea and vomiting 9.4% versus 8%, chills 9.2% versus 6.4%.  

-- immediate solicited reactions occurring within 30 minutes of vaccination were infrequent and not much difference between vaccine and placebo. There were no episodes of anaphylaxis was severe hypersensitivity 

 

 Commentary:  

-The current study found striking protective efficacy from mRNA-based vaccine. This Moderna study replicates the results of the Pfizer one (see http://gmodestmedblogs.blogspot.com/2020/12/covid-pfizer-vaccine-review.html), adding credence both to the efficacy and the limited really bad adverse effects in the first 3-4 months after the vaccine (it is always more reassuring that the results were replicated by another drug company with a slightly different drug) 

-- To me, perhaps the most important unanswered question is whether these mRNA vaccines prevent infection completely (including asymptomatic infection), or do they make infection minimally symptomatic/asymptomatic?? And, if asymptomatic infection is not prevented, how long is the asymptomatic infection transmissible to others?

    -- Part of the reason this is so important is that vaccinated people still could be a reservoir for the virus and transmit the virus to unvaccinated people. Asymptomatic infections, especially if having prolonged transmissibility, would result in a continuing reservoir for new infections in the longish run. I.e., herd immunity will be hard to achieve 

    -- another major concern is that the longer the virus is around and infecting people, the more likelihood it will develop important genetic mutations, which could be either more virulent than the prior ones, more transmissible, or even mutate enough that our current vaccine would not be effective 

        -- in this light, a new coronavirus variant was identified in the UK, VUI-202012/01, having 17 mutation changes, one of which (N501Y) is in the spike protein that binds to the ACE2 receptor (thereby potentially affecting viral transmissibility, and perhaps associated with a surge in parts of the UK. Many details are still pending (see https://www.bmj.com/content/371/bmj.m4857 ) 

    -- and, we do not know if those with asymptomatic infection are or are not susceptible to some of the long time, known effects of Covid infection, including myocarditis (which conceivably could become evident much later) 

--there was one infection in the placebo group (of a total of 334) of a patient with a prior Covid infection, reinforcing that this can happen (though quite uncommonly), though also that it is quite uncommon (ie, it still makes sense to vaccinate them)

 

--How much will this high-tech modern vaccine cost, you might ask. As per usual, more in the US than Europe (see https://www.nytimes.com/2020/12/18/upshot/coronavirus-vaccines-prices-europe-united-states.html?auth=login-email&login=email ). Pfizer is set at $19.50/dose (Europe $14.70/dose). Moderna at $25-37/dose ($15/dose in the US, decreased because taxpayers paid billions of dollars and scientific help to create it. of, note this is about 1/10 the price of the zoster vaccine (which many of my patients could not afford and went without, despite having Medicare). or about 1/2 the price of a single pill of generic Viagra. just goes to show you what bulk purchasing can do (see the Congressional Budget Office report that in 2030, a single-payer system, including everyone, would save up to a $0.7 Trillion over current system (which insures far fewer than everyone...): see Medicare for all saves money CBO report 2020 in dropbox, or https://www.cbo.gov/system/files/2020-12/56811-Single-Payer.pdf ). thanks to Paul Susman for sending me this. 

 

-- Though there seemed to be impressive data suggesting efficacy 14 days after the first dose of vaccine; this was a post hoc analysis and there were not huge numbers of patients, so we cannot conclude definitively that one dose of vaccine is sufficient. We also don’t know if the immunologic response or infection rate would be as sustained after one dose of vaccine. But these data, as well as those in the Pfizer study, do suggest significant clinical benefit within 2 to 3 weeks of the first vaccine, and the efficacy of a single dose injection should be studied (which would increase the number of people who could be vaccinated sooner). And, if necessary, a subsequent booster vaccine could be given months to years later, as is often done with older, traditional vaccines 

 

-- there was a suggestion that the vaccine worked best for those at higher risk of severe infections: 1 vs 24 cases, than those at lower risk: 4 vs 66 infections. Which would support the above concern about asymptomatic issue (ie, a shift to less severe infections noted above). But these were small numbers. 

    -- that being said, it is quite a good time now to do a more complete study: lots of SARS-CoV-2 around, easy to get large numbers of people, and can get nasal swabs weekly to assess asymptomatic infection in vaccinated vs not (trying to control for variables relevant to those who choose vaccination vs not), or even now getting many nasal samples from those randomized in the initial trial. Best to see if the positives are potentially infectious (ie, viral cultures, since PCR will pick up dead virus) 

    -- new data (which is remarkably limited) did suggest that Moderna vaccine might be effective against asymptomatic infection (pre-dose 1 and pre-dose 2 nasopharyngeal swabs were done), finding that 14 (0.1%) of those vaccinated vs 38 (0.3%) of the placebo group had positive PCRs before the second test but negative before the first test (see https://www.fda.gov/media/144453/download ) 

 

limitations: 

-- those under 18 and those who are pregnant or lactating were excluded, limiting generalizability. That being said there have been some animal studies suggesting the vaccine was safe in pregnancy. 

    -- there were 13 pregnancies during the trial, but the number was too small to be evaluable; there was one spontaneous and one elective abortion, both in the placebo group 

-- though there are many fewer exclusion criteria than in the Pfizer trial, one concern is that they have no patients identified as having a chronic inflammatory condition. This has been a concern about mRNA vaccines, which can stimulate a significant inflammatory response and potentially severe adverse outcomes. (Though as noted in http://gmodestmedblogs.blogspot.com/2020/12/covid-pfizer-vaccine-review.html , a general inflammatory response to vaccine tends to lead to more immunogenicity). It is notable that no patients i the Moderna trial with rheumatologic disease were identified. and, it would have been great if they had baseline inflammatory markers, such as CRP

-- it is currently unknown how long vaccine effectiveness will persist.  Time will tell… 

--the people enrolled in this study are likely very different from the general population, which may well have more medical comorbidities, and more likelihood of acquiring Covid infection (this large patient group in Moderna was really pretty healthy, per demographics above)

    --and, there are no data presented on any of the psychosocial factors, such as housing conditions, crowding, financial/housing/food security, income inequalities, depression/anxiety, use of personal protective equipment, social distancing, etc etc, which could affect SARS-CoV-2 transmission 

-- and, as noted above, there are very limited on the effects of vaccine on asymptomatic transmission 

-- also, some of the adverse events attributed to the vaccine could have been from mild Covid infections, attributed by the patients to the vaccine, the subsequent PCR test might have become negative, so some Covid might have been missed, potentially in both the vaccine and placebo groups

-- there were too few infections overall in the subgroup analyses to be certain. For better or worse, we will now find out how these subgroups will do, given the approval of the vaccine for the general population 

 

So, 

--very impressive results from the Moderna vaccine. And, notably reproducing those of the Pfizer vaccine almost exactly, adding increased credence to the remarkable ability of these mRNA vaccines to work (and being much more effective than many of the older vaccines)

--adverse effects are quite common, but rarely really bad. And we know the adverse effects of Covid can be really bad 

--since we do not have significant data on asymptomatic transmission of the virus to others: 

    --we do know that the vaccinated individual is highly (but not completely) protected 

    --but there is the very real potential that vaccinated people will be a reservoir for infecting others (and potentially leading to bad viral mutations, as above). 

    --which means: vaccinated people really need to continue with aggressive use of masks, social distancing, avoiding indoor exposure to others to the extent possible, especially minimizing being around people who are at high risk of a severe Covid outcome (especially if they have not been vaccinated) 

    --which means: not letting our guard down just because we have been vaccinated….. 

geoff

 

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