In medicine, there is a thin line between fact and speculation. Unfortunately, a significant portion of the information we read and hear in the setting of the pandemic is speculative. For instance, when US president Mr Trump declared in March that hydroxychloroquine was ‘a game-changer’, large sections of the world population mistook it for a fact, while it was pure speculation. The amount of effort and money that was eventually wasted in proving this speculation wrong could have been better utilised during the pandemic.
Although it might be helpful while planning research studies, speculation is often corrupted with bias and emotion. Likewise, in the fast-changing field of vaccines, speculation is rampant. This has resulted in irrational anxiety, and unrealistic hope.
The objective of this article is to describe the facts about vaccines with minimal jargon, separating the knowns from the unknowns to the extent possible. As science continues to advance, some of this information is subject to change.
1. Vaccines are not like a light switch that turns off the pandemic. Even after they become available, social distancing measures will continue until the pandemic abates. In other words, vaccines represent only one component of the anti— pandemic strategy.
2. Efficacy is the percentage reduction of disease observed in the vaccine group, compared to the placebo group, measured under ideal conditions. This will be higher than effectiveness, which measures the same outcome in ‘real world conditions’- that is outside of a carefully controlled clinical trial.
3. Efficacy measured within the first two months after completing vaccination will be invariably high due to high antibody levels. As expected, preliminary results have reported 62-95% efficacy. It is important to see how these numbers hold up in the 6th, 12th, and 24th months, as antibody titres slowly drop.
4. There is plenty of debate about what must be taken as the end-point to be measured as proof of efficacy of a COVID vaccine. Pfizer, Moderna and AstraOxford chose symptomatic COVID-19 as the ‘primary endpoint’. This means that asymptomatic infections are not counted as a primary endpoint.
Besides, the criteria for diagnosing symptomatic COVID-19 are different for each vaccine. Other potential primary end-points that could have been used include the total number of all infections (including asymptomatic SARS-CoV-2 infection), number of deaths or number of people requiring ventilator support.
Choosing a primary endpoint in a clinical trial is somewhat like choosing a single feature of a car model to compare between different manufacturers. Some people might look at reliability; a few will prefer to compare engine performance in horsepower and yet others may compare mileage.
5. The process of bringing out a vaccine involves building the vaccine, and then testing its safety as well as efficacy. While technology enables quicker development of a vaccine, unfortunately we cannot speed up time of observation. Safety assessment is done over a period of time, and this cannot be shortcircuited. It is almost as though the first half of a long movie has been fastforwarded, but the second half can only play out at normal speed.
This is the reason why the FDA has asked for a minimum of two-months follow-up data after completion of vaccination before applying for emergency authorization.
6. Short-term safety is reasonably certain because these vaccines have been tested in tens of thousands of volunteers under close supervision. However, long-term effects are unknown. Unknown does not necessarily imply unsafe.
7. Prolonged observation (phase 4 trials) of vast numbers of vaccinated people is the only method to detect very rare events, whether it is short term or long-term. By definition, very rare events are those that occur in fewer than 1 in 10,000 people. Such effects need not manifest even when tens of thousands of people have been vaccinated.
8. It is important to know the technical difference between severe and serious adverse events, while interpreting vaccine literature. Serious side effect is an event leading to hospitalization, significant disability or death. Severe side effect is a broader term which also includes non-life-threatening outcomes.
9. Two events occurring in sequence need not necessarily be connected with each other. All human beings are subject to random occurrence of serious disease such as heart attacks, sudden deaths, infections, allergies, cancer, stroke and other neurological disease. Also called ‘background rates’, they vary between countries due to several reasons including difference in monitoring systems.
When such a random event occurs in a person who has also received a vaccine recently, it could get falsely attributed to the vaccine. In certain cases, it will take substantial expertise to decide if an event was related or unrelated to the vaccine.
10. The concept of risk means different things to different people. What is considered routine by one person might be called dangerous by another.
11. The success of a vaccine in controlling a pandemic depends on how many people actually receive it. For instance, a US study has projected that if a vaccine of 80% efficacy is used, at least 75% of the population will need to be vaccinated to achieve adequate immunity levels in the community.
12. A number of people have said they will not take the vaccine as soon as it gets released. Whether this fraction will increase or decrease is unknown. Public trust is a key element here. A recent survey in India showed that 59% are unwilling to take it right away. In US, over 70% of the nurses were sceptical about the new vaccines. It is natural “not to want to be the first to take the plunge”.
13. Younger adults know they are at low risk of dying from SARS-CoV-2 virus, and might decide it is worth taking the (known) risk of natural infection rather than the (unknown) risk of a man-made vaccine. It is not easy to find fault with that viewpoint.
14. Human immune response against different types of viruses is variable. Though all viruses induce an immune response, not all immune responses confer immunity. For instance, in the case of viruses like measles and chicken pox, immune response following infection or vaccine provides life-long immunity from another attack.
However, in the case of viruses belonging to the Corona virus family, that is not the case; reinfections are the rule. In the case of other viruses in this family, immunity from one infection lasts only for a few months to years.
15. An important question that comes up therefore, is whether people who had been infected once by the SARS-CoV-2 virus could get it again. As is the rule with the Corona virus family, re-infections are known to occur with the SARS-CoV-2 virus, but this fact have consistently been played down by the academics.
Although considered ‘rare’, their true incidence will never be known. Several doctors have seen cases of reinfection (11) in their practice, but have not published these cases due to practical difficulties. Academic publishing is timeconsuming. It requires extra effort, institutional patronage, publishing experience and involves expense, for instance to perform genotyping during both the episodes of infection in the same patient.
Unfortunately, what is not published is considered non-existent by a large segment of the academic community. Among the few reported cases of reinfections, about half have been more severe than the first.
It is unknown at this time whether those who receive a vaccine will get reinfected, how many will get re-infected, what the severity will be, what the average duration of protection is and how often a booster dose will be required.
16. There are some experts who believe that a vaccine will provide greater protection than a natural infection, but this is speculative at this point. There are early reports that vaccines, through their standardised dose and targeted approach, generate higher neutralizing antibody titres than natural infection.
As we are already 12 months into the pandemic, researchers have had the opportunity to observe the natural course of COVID-19 survivors over a period of several months. Studies based on these observations have reported the persistence of memory B cells and T cells--which could be markers of long-term protection following natural infection.
However, whether vaccines will generate the same amount of memory B cells and T cells, and if this actually translates into long term protection, will only become known with time. It is important to know that the mere presence of antibodies, B cells or T cells does not necessarily imply that the body is protected from future infection by the SARS-CoV-2 virus.
To put this in perspective, making a new vaccine can be compared to building a kite at home. Regardless of the technique or materials used such as newspaper, glue, reed, thread and attachments, what matters in the end is how well the kite flies in the wind. A better-looking kite made of expensive material need not always become the winner. Likewise, until they are tested in clinical trials, it is impossible to predict which vaccine will work the best.
17. Most of the frontrunner vaccines are directed against the spike protein, which is essentially the landing pad of the virus. As the virus attaches to our cell surface, this landing pad works like a key that turns a lock located on the cell membrane- called the ACE-2 receptor. This is an important first step in viral infection, which vaccines are hoping to block.
If the real virus attacks us in the future, these antibodies act like a piece of bubble gum or superglue that blocks the key from opening the lock. Thus, the virus is unable to land, and infection is thwarted before it sets in.
Early results of the vaccine trials are consistent with this explanation; those who received the vaccine have had fewer symptomatic infections compared to the placebo group. In addition, the Pfizer and Moderna trials confirm that those who
received the vaccine had fewer severe infections. However, we do not know if any of the vaccines reduced the number of asymptomatic infections yet. The interim analysis published on 8 December in Lancet by Astra-Oxford vaccine shows no significant overall difference in asymptomatic infections between vaccinated and control groups.
18. Since vaccines are not proven yet to reduce asymptomatic infections or nasal shedding of virus in man, we do not know if vaccination will reduce the spread of virus. This is not the same as reducing the risk of developing symptomatic disease, which was the end-point measured in the studies reported so far.
19. Vaccination is therefore not a guarantee against infection. Asymptomatic infections could occur among vaccinated individuals. Such people may spread the disease while socialising because they feel well, and by ignoring precautionary measures because they believe they are immune.
20. How the above factor fits into the pandemic spread equation is unclear. Superspreading events could occur as a result of this new-found confidence. Socially active caregivers of the elderly might end up giving them the virus.
21. While data released by vaccine manufacturers might be accurate, it isn’t considered as dependable or comprehensive as that published in a reputed medical journal after peer review. Subgroup analysis could reveal pitfalls in interpretation that the overall percentages might have overlooked. Apart from Astra-Oxford, (20) who has just published the first interim analysis, none of the frontline vaccine-makers have officially published the complete efficacy results of their phase 3 trials yet—at the time of writing this article.
22. According to the data released by the manufacturers, the overall number of symptomatic infections is lower among those who received vaccine, compared to placebo. However, the exact number of infections in vaccinated and placebo groups among the elderly is not known yet. Pfizer and Moderna trials have included a considerable number of elderly participants, results are awaited.
The just-published interim results of Astra-Oxford vaccine have limited data on infections in elderly participants, although the immunogenicity of the vaccine was previously shown to be similar across all adult age groups.
The picture will be clear after each one of the final trial results are published.
23. Random reports of serious side effects following vaccination can generate unreasonable anxiety amounting to panic. Such panic is comparable to people reacting to the story of a plane crash and then deciding that flying is unsafe.
Some of them will not be convinced even if they are informed afterwards that statistically, flying is safer than driving a car.
However, it must be remembered that unlike a medication given to cure someone who is already sick, vaccines are given to previously healthy people. Therefore, any serious adverse outcomes that occur are measured using a different yardstick.
24. Fake news about vaccine adverse outcomes is perhaps the greatest threat that will affect public confidence. Fake news travels fast on social media platforms, helped along by people who readily share among their contacts without making an attempt at verification.
25. As is the case with any product, there could be better vaccines in the pipeline. However, doing more placebo-controlled trials is almost ruled out because it is unethical to ask someone to take a placebo when an approved vaccine is already in use. Besides, future volunteers might prefer to get a known vaccine rather than an unknown product, and might not be willing to participate in a trial. The new vaccines will likely end up being compared to existing vaccines.
In summary, it is remarkable that vaccines have been created, tested in trials and approval processes commenced in less than a year’s time. Efficacy and safety are two key aspects of a vaccine as described in some detail above. The preliminary results on vaccines are encouraging, but long-term observation is required to obtain a clearer picture. There are several unknowns at this time, which is only natural in the setting of a pandemic involving a new virus. Unknowns must be rectified with scientific evidence, not by speculation. Building public trust is important at this juncture. Trust is a commodity that can’t be bought or manufactured, and has substantial cultural variation. A few of the factors that decide trust are transparency, accountability and effective communication.
Dr Rajeev Jayadevan MD(Vellore), DNB, MRCP, American Board Certification in Medicine and Gastroenterology
Senior Consultant Gastroenterologist and Deputy Medical Director, Sunrise Group of Hospitals
Past President, Indian Medical Association Cochin