Covid-19: Moderna vaccine is nearly 95% effective, trial involving high risk and elderly people showsBMJ 2020; 371 doi: https://doi.org/10.1136/bmj.m4471 (Published 17 November 2020) Cite this as: BMJ 2020;371:m4471
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Re: Covid-19: Moderna vaccine is nearly 95% effective, trial involving high risk and elderly people shows
The method of testing for symptoms as described in the Moderna protocol was not monitored until day 42, 14 days after the second dose at day 28 , why was there no monitoring immediately within 5 days after the first shot and second shot, when symptoms would be noticeable, waiting 14 days after the second shot would eliminate test subjects that showed positive side effects because the majority of symptoms would have resolved within 8 days after infection.
Competing interests: No competing interests
The phase III clinical trial results of the two frontrunner CoViD-19 vaccines developed by Pfizer  and Moderna  has claimed ~95% efficacy in their interim analysis. There are many reasons why such efficacy claims are premature and are likely to be proven incorrect in the long term.
First, the Moderna’s claim is based on an interim analysis of vaccine efficacy from only 95 confirmed cases of 30,000 subjects in the trial; this is 0.32% of the total study subjects. If trial subjects are equally divided into vaccine and placebo groups, then the 90 and 5 confirmed CoViD-19 cases in the placebo and vaccine groups represents 0.6% and 0.03%, respectively. The prevalence of CoViD-19 confirmed positive cases in the USA  is currently estimated as ~4% of the total US population. Presuming the vaccine efficacy at 100% as the best-case scenario and if 4% of subjects in the placebo group were to contract the virus, at least 600 positive cases are expected in the trial. In contrast, the interim analysis was performed at only 95 confirmed cases, which is too early. The thresholds for the primary efficacy endpoints should have been set nearer to the geographical prevalence rates of CoViD-19. Currently, 99.4% of subjects in the placebo group have not contracted the virus either. This does not mean that the placebo is equally effective in preventing CoViD-19, it is just a matter of time. A similar issue is noted with Pfizer’s vaccine efficacy claims.
Second, the trial subjects are living a new normal (social distancing, wearing masks, hand hygiene etc), which means that their chances of contracting the virus are already low (currently 4 in 100 in the USA). This would mean that we do not know if the subjects in the vaccine group were protected due to the vaccine or it is just because they have not had a contact yet. The definitive approach could involve deliberately challenging the trial subjects with the virus, like in preclinical trials, however, it is unlikely due to ethical and safety implications. In the absence of any definitive challenge test, it becomes imperative to not rush to conclude efficacy just within weeks of vaccination.
Third, we do not know the antibody levels of the study subjects. What is the baseline antibodies titer in trial subjects against different coronaviruses? Have all subjects in the vaccine group produced antibodies and shown a cellular immune response? If yes, how the levels are like in comparison with the placebo group? Many in the placebo groups may have produced antibodies naturally should they had a viral contact before joining the trial. What is the antibody titer of the 95 subjects who are tested positive, particularly the five subjects who contracted the disease in the vaccine group? Have they all produced antibodies, how much, and what’s the T-cell response is like in them compared to other subjects?
Fourth, whether the CoViD-19 test offered to all subjects in the trial before the interim assessment was made or restricted to symptomatic subjects only? If only selected subjects were offered the test, how the selection/judgement bias was mitigated? Moreover, it is likely to have a potential overlap of CoViD-19 symptoms with vaccine side effects hence another reason why all subjects should have been tested. Were trial subjects permitted to use OTC remedies for their post-vaccination symptoms and how this impacted on their probability of being offered a CoViD-19 test? What about the asymptomatic carriers – those who have had no symptoms but may still have contracted the virus?
Fifth, how long the antibodies will live in vaccine subjects? The interim analysis was performed just two weeks after the subjects received a second dose of the vaccine which is certainly not enough time to decide on a global vaccination campaign. It is important to know if further booster doses may be required and whether the cellular immunity offers any future protection should the antibody titer falls.
Sixth, the vaccine was tested against a placebo group that was only given a normal saline injection as a negative control. It would have been wise to include a BCG control group to enable a comparative assessment of CoViD-19 vaccine efficacy against the BCG vaccine which is already on immunisation schedule in many countries. BCG vaccine was hypothesised earlier in the pandemic  to be a potential predictor of the low CoViD-19 associated mortality seen in parts of the world. BCG has also shown some clinical efficacy against respiratory viruses and interestingly have also shown a protective effect in elderly subjects from some respiratory tract viral infections [5,6].
Seventh, since the vaccine is to be rolled out globally, the efficacy of vaccine may be established against a range of genetic variants of SARS-CoV-2 that are currently prevalent across the world. It may be interesting to spot the genetic variations where the vaccine did not respond. This will help in identifying potential demographics that are unlikely to benefit from a particular vaccine.
In light of the above, the actual efficacy of the vaccine is likely to be much lower. This publicity, no doubt, has given the world great hope but can be disappointing to the public when the long-term efficacy was not as good as claimed in the interim assessment. Albeit not a surprise to many clinicians and scientists, the public may react badly. This may also fuel anti-vaccine thoughts and is not in the greater interest of public safety and may jeopardise their trust in science and medicine. Moreover, this is going to be the first mRNA-based vaccine being developed for the mass public use and a longer-term safety and efficacy assessment is inevitable. The mass publicity and celebration of the interim results, therefore, was a very bad idea and likely to have adverse implications.
Competing interests: No competing interests
Dear EditorMODERNA VACCINE IS NEARLY 95% EFFECTIVE, BUT NNTV = 176 TO 1370
Moderna’s phase III trial has shown that, so far, the vaccine is 94.5% effective. (Mahase, BMJ 2020;371:m4471, November 17) As with the Pfizer vaccine news release, few numbers are provided, but we can approximate the absolute risk reduction for a vaccinated individual and the Number Needed To Vaccinate (NNTV): There were 90 cases of Covid-19 illness in a placebo group of 15,000 (0.006) and 5 cases in a vaccine group of 15,000 (0.00033). This yields an absolute risk reduction of 0.00567 and NNTV = 176 (1/0.00567). There were 11 severe illnesses, all in the placebo group, for an absolute risk reduction of 0.00073 and NNTV = 1370. So to prevent one severe illness 1370 individuals must be vaccinated. The other 1369 individuals are not saved from a severe illness, but are subject to vaccine adverse effects, whatever they may be and whenever we learn about them.
How does this compare with other vaccines? Before the measles vaccine became available 90% of children in North America had measles by age 10. Two doses of the vaccine are about 95% effective, so a vaccinated individual’s risk is reduced by 0.855 (0.90 x 0.95), and the NNTV = 1.17 (1/0.855); this is extraordinarily effective……On the other hand, it has been calculated that to prevent a single case of invasive meningococcal disease in North American infants with 3 doses of 4CMenB vaccine at least 33,000 infants must be vaccinated, so NNTV is > 33,000! (Dang et al, BMC Infect Dis 2012;12:202)
Shouldn’t absolute risk reduction be reported so individuals can make fully informed decisions about vaccinations?
ALLAN S. CUNNINGHAM 22 November 2020
Competing interests: No competing interests
We read with great interest your news item on the Moderna vaccine (1). Two COVID-19 vaccines including the one referred to in your news piece have been developed with promising efficacy so far. The vaccines developed by Pfizer and BioNTech (2) and Moderna (3) have shown efficacies of 94% and 95% respectively in clinical trials. Unfortunately, we only have press releases and not peer reviewed scientific manuscripts. There are already efforts underway to make the Pfizer vaccine available to the UK population (4). In the COVID era we seemed to have forgotten the golden rule of Ingelfinger (5). Countries appear to be adopting different approaches in prioritising who should get the vaccine (6,7). The Joint Committee on Vaccination and Immunisation (JCVI) has published government guidance on which groups should be prioritised for the COVID vaccine (6). The JCVI interim advice has prioritised vaccination on an age-based order and prioritised health and social care workers. However, France has taken a different approach and prioritised high-risk occupations, including shop workers, school staff, transport staff such as taxi drivers, hospitality workers and abattoir staff (8).
Furthermore, France is currently undertaking a public consultation on who to prioritise (8). As the vaccine will be largely funded by the taxpayer seeking the views from the public appears appropriate. However, it remains to be seen the response of the public and its utility in such complex issues including a rapidly developed vaccine for a novel disease which needs to be deployed at a great speed.
In the early part of the pandemic when there was scarcity of testing capacity questions were raised when members of the Cabinet including the Health Secretary were tested (9). Hence it is essential that we have clear and transparent protocols and criteria on who to offer the vaccine in the early stages of the vaccination programme. When further testing capacity became available the government extended the testing to frontline workers and expanded the definition of these workers (10). We wonder if the government should consider adopting a similar approach of including frontline workers apart from health and care home staff in the initial priority group for COVID vaccination. One key question is whether anyone involved in the COVID response including local authority Public Health teams led by the Directors of Public Health (11) should be on the priority list? This list should also be expanded to include leadership at the central, regional and local level who are leading the fight against COVID as they will be key part of the COVID pandemic response workforce.
Dr Xinming Yu, Foundation Year 2 Doctor in Public Health
West Suffolk Hospital and Public Health Suffolk
Dr Padmanabhan Badrinath, Consultant in Public Health Medicine,
Public Health Suffolk, Suffolk County Council.
1. Mahase E. Covid-19: Moderna vaccine is nearly 95% effective, trial involving high risk and elderly people shows. BMJ [Internet]. 2020 Nov 17 [cited 2020 Nov 18];371. Available from: https://www.bmj.com/content/371/bmj.m4471
2. Pfizer and BioNTech Conclude Phase 3 Study of COVID-19 Vaccine Candidate, Meeting All Primary Efficacy Endpoints | Pfizer [Internet]. [cited 2020 Nov 18]. Available from: https://www.pfizer.com/news/press-release/press-release-detail/pfizer-an...
3. Moderna’s COVID-19 Vaccine Candidate Meets its Primary Efficacy Endpoint in the First Interim Analysis of the Phase 3 COVE Study | Moderna, Inc. [Internet]. [cited 2020 Nov 18]. Available from: https://investors.modernatx.com/news-releases/news-release-details/moder...
4. UK government response to Pfizer/BioNTech’s publication of efficacy data of their COVID-19 vaccine [Internet]. GOV.UK. [cited 2020 Nov 18]. Available from: https://www.gov.uk/government/news/uk-government-response-to-pfizerbiont...
5. Have we abandoned the Inglefinger rule in the COVID era? 2020 Nov 15 [cited 2020 Nov 18]; Available from: https://www.bmj.com/content/369/bmj.m2279/rr-1
6. France C. France sets out future Covid-19 vaccine priority plan [Internet]. [cited 2020 Nov 18]. Available from: https://www.connexionfrance.com/French-news/France-sets-out-future-Covid...
7. JCVI: updated interim advice on priority groups for COVID-19 vaccination [Internet]. GOV.UK. [cited 2020 Nov 18]. Available from: https://www.gov.uk/government/publications/priority-groups-for-coronavir...
8. Roope L, Clarke P, Duch R. Who should get the coronavirus vaccine first? France and the UK have different answers [Internet]. The Conversation. [cited 2020 Nov 18]. Available from: http://theconversation.com/who-should-get-the-coronavirus-vaccine-first-...
9. Prime minister Boris Johnson and health secretary Matt Hancock infected with COVID-19 | GPonline [Internet]. [cited 2020 Nov 18]. Available from: https://www.gponline.com/prime-minister-boris-johnson-health-secretary-m...
10. Government to extend testing for coronavirus to more frontline workers [Internet]. GOV.UK. [cited 2020 Nov 18]. Available from: https://www.gov.uk/government/news/government-to-extend-testing-for-coro...
11. Public health on the frontline: responding to COVID-19 | Local Government Association [Internet]. [cited 2020 Nov 18]. Available from: https://www.local.gov.uk/our-support/coronavirus-information-councils/co...
Dr Xinming Yu, Foundation Year 2 Doctor in Public Health
West Suffolk Hospital and Directorate of Public Health
Dr Padmanabhan Badrinath, Consultant in Public Health Medicine, Suffolk County Council & Associate Clinical Lecturer, University of Cambridge.
Directorate of Public Health, Endeavour House, Suffolk County Council, Ipswich, IP1 2BX. firstname.lastname@example.org
Disclaimer: The views expressed here are the personal views the authors and in no way represent the views of their employer, Suffolk County Council.
Conflict of interest: Both the authors work in a local authority Public Health Department and are part of the local COVID response.
Competing interests: Both the authors work in a local authority Public Health Department and are part of the local COVID response.