Why Pfizer's or Moderna's CoViD-19 vaccine cannot be 95% effective?
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