Recently, The Lancet Infectious Diseases published the first study that confirms a COVID-19 re-infection in the USA. Researchers verified it via genetic sequencing. The patient tested positive for two distinct SARS-CoV-2 infections within 48 days, confirming that a second infection can occur within a short time frame and can be more severe.

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Case study

It all started when a 25-year-old man who resides in Washoe County in the US state of Nevada presented to health authorities on two occasions with symptoms of viral infection, once at a community testing event in April, 2020, and a second time to primary care, then hospital at the end of May and beginning of June, 2020.

Researchers obtained nasopharyngeal swabs from the patient at each presentation and twice during follow-up. They carried out nucleic acid amplification testing to confirm SARS-CoV-2 infection. They did next-generation sequencing of SARS-CoV-2 extracted from nasopharyngeal swabs.

They used two different bioinformatic methodologies to assess sequence data. Researchers used a short tandem repeat marker for fragment analysis to confirm that samples from both infections came from the same individual.

The patient’s second infection was more severe, resulting in hospitalisation with oxygen support; it indicates that previous exposure to COVID-19 may not translate to guaranteed total immunity, but that further research into re-infections is required.

The patient may remain an asymptomatic carrier. These studies may lead to exciting discoveries on immunity and such other not so well known aspects of the pandemic. The study may be a maiden step to answer key questions such as:

• How common is re-infection?
• Are re-infections more or less severe than the first?
• What implications do re-infections have for vaccine prospects?

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Urgent need to take precautions

The authors cautioned that all individuals—whether previously diagnosed or not—should take identical precautions including social distancing, wearing face masks, and hand-washing to prevent infection with SARS-CoV-2.

The patient has since been discharged from the hospital and has recovered from the second infection.

At the very outset, the researchers stated that infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to a detectable immune response, but the susceptibility of previously infected individuals to re-infection with SARS-CoV-2 is not well understood.

“SARS-CoV-2 infection results in generation of neutralising antibodies in patients. However, the degree to which this immune response indicates a protective immunity to subsequent infection with SARS-CoV-2 has not yet been elucidated,” the researchers said.

They found that in studies of immunity to other coronaviruses, loss of immunity can occur within 1–3 years. According to them, cases of primary illness due to infection followed by a discrete secondary infection or illness with the same biological agent can best be ascertained as distinct infection events by genetic analysis of the agents associated with each illness event.

In a press release published by the journal, Mark Pandori, PhD, of the Nevada State Public Health Laboratory, the University of Nevada, Reno School of Medicine and lead author of the study stated that there are still many unknowns about SARS-CoV-2 infections and the immune system’s response, but their findings signal that a previous SARS-CoV-2 infection may not necessarily protect against future infection.

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Other instances of re-infections

People with SARS-CoV-2, may continue to test positive for several months without being sick or infectious. Researchers confirm a re-infection when testing shows each virus’ genetic makeup is different to a degree which cannot be explained through in-vivo evolution.

Based on literature survey covering only publications in English, the researchers in the Lancet study identified four other reports of secondary infection events with SARS-CoV-2, other researchers have published from Hong Kong, the Netherlands and Belgium, and Ecuador.

However, only the Ecuador- re-infection case displayed worse disease outcomes than the first infection.

[BNO News published details of 23 cases of re-infections, the latest being on 12 October 2020. Reinfection appears to be extremely rare, 23 in 38 million cases!]

“We need more research to understand how long immunity may last for people exposed to SARS-CoV-2 and why some of these second infections, while rare, are presenting as more severe,” Pandori said.

“So far, we’ve only seen a handful of re-infection cases, but that doesn’t mean there aren’t more, especially as many cases of COVID-19 are asymptomatic. Right now, we can only speculate about the cause of re-infection,” he added.

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Differences in the status of the re-infected patients

There were clear differences in the status of re-infected patients.

Similar to observations with the re-infection case in Ecuador, the US patient showed increased symptom severity in their second infection, whereas the cases from Belgium, the Netherlands, and Hong Kong did not show a difference in the severity of symptoms.

According to the authors, the severity of the second infection may be because possibly the patient subsequently encountered a very high dose of the virus which caused a more acute reaction the second time; may be the patient has come in contact with a more virulent version of the virus.

A third hypothesis is that a mechanism of antibody dependent enhancement (meaning the presence of antibodies can make a subsequent infection worse) may be the cause, which researchers saw previously with the SARS-CoV beta-coronavirus as well as other diseases, such as dengue fever.

The authors explain that there is a very slim possibility of a continuous infection involving some form of deactivation/reactivation. They knew that for such a hypothesis to be true would require a mutational rate of SARS-CoV-2 that has not currently been observed.

Another explanation would be a simultaneous co-infection of both strains of the virus. However, this would mean that the second strain would have gone undetected in April 2020, and conversely, the first strain would need to be depleted before the June 2020 collection. This possibility does not account for the genotype switch in this patient.

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Limitations of the study

The authors acknowledge the limitations of the study: they were not able to undertake any evaluation of the immune response to the first episode of SARS-CoV-2 infection nor were they able to assess fully, the efficacy of the immune responses (e.g. neutralising antibody titres) during the second episode.

This case and other confirmed re-infection cases occurred among patients who displayed COVID-19 symptoms, meaning there is the possibility that many infections and/or re-infections among individuals may be asymptomatic and therefore likely to remain undetected under current testing and monitoring practices.

“Overall, there is a lack of comprehensive genomic sequencing of positive COVID-19 cases both in the USA and worldwide, as well as a lack of screening and testing, which limits the ability of researchers and public health officials to diagnose, monitor, and obtain genetic tracking for the virus,” Pandori said.

In an accompanying commentary, Dr. Akiko Iwasaki, a professor of Immunobiology and Molecular, Cellular and Developmental Biology at Yale University, USA, who was not involved in the study, explored what is known about the current confirmed cases of re-infection, and the possible implications for public health and vaccinations. She is the right person to comment on the paper as she was specialising in studies of re-infection.

“As more cases of re-infection surface, the scientific community will have the opportunity to understand better the correlates of protection and how frequently natural infections with SARS-CoV-2 induce that level of immunity. This information is key to understanding which vaccines are capable of crossing that threshold to confer individual and herd immunity,” she added.

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Experts’ comments

In a press release from the Science Media Centre, London, Dr. Simon Clarke, Associate Professor of Cellular Microbiology at the University of Reading, said:

“The possibility of re-infection with the coronavirus has been something that medical science has been waiting to answer. Initial over-confident predictions that once you’d had it, you couldn’t get it again, were opinions rather than facts.”

He clarified that it is becoming increasingly clear that re-infections are possible, but we can’t yet know how common this will be.

“It might prove to be a rare phenomenon, but it’s equally possible that these could be the first few cases and that there are many more to come,” he added.

“The implications of more widespread re-infection are that herd immunity would not work. This provides further scientific evidence for extreme caution in proposing policies that allow COVID-19 to rip through the younger population while attempting to shield the elderly and vulnerable – even if that were possible, which it probably isn’t. If people can be re-infected easily, it could also have implications for vaccination programmes as well as our understanding of when and how the pandemic will end,” he cautioned.

Prof. Paul Hunter, Professor in Medicine, the University of East Anglia (UEA), said:

“I think most of us have thought that re-infection with COVID-19 was likely to become common as individuals’ immunity levels declined post infection. However, the findings in the paper by Tillett and colleagues are very concerning both from the point of view of the very short time between the two infections and the fact that the second illness was more severe than the first. Until this and one other recent report from Ecuador I for one assumed that any second infection was likely after only a few months and then most likely to be less severe, at least in otherwise immune competent individuals. Indeed, apart from this US and the Ecuadorian cases, other reports of re-infection have tended to be asymptomatic.

“Given the fact that to date over 37 million people have had the infection we would have expected to have heard of many more incidents if such very early re-infections with severe illness were common. Nevertheless, repeat infections do occur with different strains and I suspect many more will be found over coming months as immunity declines in individuals after infection. It is too early to say how common increased severity of illness associated with a second infection will be. It is likely that the risk of more severe disease during a re-infection will be overestimated from published data as mild and asymptomatic individuals are much less likely to be screened than repeat symptomatic cases.

“It is too early to say for certain what the implications of these findings are for any immunisation programme. But these findings reinforce the point that we still do not know enough about the immune response to this infection. We need to study such re-infections with severe illness in order to identify whether there are specific genetic or other factors that could explain the risk of severe disease and then hopefully prevent or reduce the severity of any infection.”

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Re-infections appear to be very infrequent. However, dedicated research on them will be rewarding. Given, the complex behaviour of this novel virus, researchers need not expect any low hanging fruit!

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

Dr. K S Parthasarathy is a former Secretary of the Atomic Energy Regulatory Board and a former Raja Ramanna Fellow, Department of Atomic Energy. A Ph.D from University of Leeds, UK, he is a medical physicist with specialization in radiation safety and regulatory matters. He was a Research Associate in the University of Virginia Medical Centre, Charlottesville, USA. He served the International Atomic Energy Agency as an expert and member in its Technical and Advisory Committees.