The immune responses of people to natural infection can be modified by immune evasion mechanisms of the virus
As on January 1, nearly 10.3 million SARS-CoV-2 cases have been reported in India, and in all about 50% of people in large urban cities and about 30% of those across India would have already been infected. The four high-risk groups that would receive the vaccine on priority in India alone amount to 300 million people, meaning 600 million doses would be required to vaccinate them.
Since vaccine shortage is expected to last at least for a few months, it may seem appealing to delay or avoid vaccinating those who have been naturally infected. But does science support such a decision?
“A small minority of those with even symptomatic infection do not end up making high levels of antibodies, and another small minority of such naturally infected people do not make long-lasting antibodies. So, all in all, it is the easiest policy to immunise people without worrying about whether they have been previously infected or not,” immunologist Dr. Satyajit Rath, formerly with the Delhi-based National Institute of Immunology, says in an email.
Dr. Gagandeep Kang, Professor of Microbiology at CMC Vellore elaborates saying that while highest levels of binding antibodies are seen in people with the most severe disease, asymptomatic infections may result in low antibody levels or even no antibodies being measured in up to 20% of people.
Besides binding antibodies, functional antibodies that block or neutralise the virus are also found in infected people. “Limited studies patients indicate that memory T cells are produced against the virus which indirectly implies that immunity is likely to be longer,” says neurovirologist Dr. V. Ravi formerly with NIMHANS.
Lack of knowledge
“At the moment, we do not know what really protects against SARS-CoV2 disease, and at what threshold, and for how long. Vaccines are made to induce a good immune response, which is expected to be more predictable than the response to infection. But immune responses in vaccinated people are still being studied, particularly to understand what is protective and how long protection lasts,” says Dr. Kang in an email. “Based on all that we know and do not know at this time, it is advised that even if you have been infected before, you should take the vaccine.”
“Both practical considerations as well as lack of precise information on how long immunity lasts after a natural infection necessitates that we do not discriminate against people, says Dr. Ravi.
Another reason why skipping vaccination in people already infected might not be advisable is the way the virus in general primes the immune system. Dr. Rath says immune responses to natural infection can be modified by immune evasion mechanisms of the virus. But vaccine formulations do not include those viral tricks, and therefore, immune responses to the vaccines are more likely to be uniform and predictable. “Yes, it is possible that vaccines can result in an immune response that does better than natural infection. We have known this for a long time,” adds Dr. Kang.
Like in the case of natural infection, vaccines too can produce responses that can be variable across people. “Virus dosage varies a great deal in natural infection, and viral immune evasion tricks work variably well in different individuals. These two sources of variation do not apply to vaccines, so variation in vaccine-generated immune responses is likely to be less than that in natural infection,” Dr. Rath explains. Dr. Ravi says that variation will depend on the type of vaccine, host age and underlying comorbidities, which generally can cause a degree of immunosuppression.
Globally, only a handful of reinfection cases have been documented so far, and a few studies show that protection from natural infection lasts over six months. Despite overwhelming evidence, it does not support skipping vaccination in those with prior infection. First, there is no evidence for how long on average protection from natural infection lasts. Also, large-scale genome sequencing studies have not been undertaken to categorically say reinfections have been just a handful.
“In principle, if infection protects against sufficient disease, it would be okay for people who have measurable protection to wait to be vaccinated. But since we do not know how long protection lasts, what constitutes a measure of protection and the logistics of getting people in priority groups back when the period of protection has waned, I think it would be challenging to establish a system that denies vaccination to those recently infected, even for a limited time,” emphasises Dr. Kang.
Another possible reason to avoid vaccinating people with prior infection is the possibility of disease exacerbation. But there is no such evidence in the case of coronavirus. For one, some phase-3 trials have not tested participants for pre-existing antibodies prior to vaccination and excluded them. And so far, there are no reports of any harm, although it is not clear if the evidence is large enough to be sure. “There is no reason to assume that we should expect a problem. Unlike dengue where this may be an issue, we do not have multiple types of viruses causing COVID-19,” she says.
If vaccination is to be done selectively, the bigger issue is of testing people for antibodies prior to vaccination. This raises several challenges — increased cost and time, logistics and manpower. “It is not really possible to operationalise pre-vaccination testing on a routine basis. We’re already learning in the U.S. that vaccinating the nation is a complicated undertaking and keeping it as simple as possible without complicated or fussy criteria might become necessary,” Dr. Peter Hotez, Professor, Departments of Pediatrics, Molecular Virology & Microbiology, Baylor College of Medicine says in an email.
Also, since antibodies wane in about six months, ascertaining the infection status in people who were infected early during the pandemic becomes even more challenging and unlikely to give answers that are of practical use or public health solution.