A nurse in a protective face mask works in an ICU at a hospital near Paris, as the COVID-19 outbreak continues in France, September 15, 2020. Photo: Reuters/Gonzalo Fuentes.
Bengaluru: As COVID-19 cases continue to rise worldwide, experts are faced with a critical question: can a person catch the disease a second time? The answer to this question influences, among other things, the prospects of the vaccine and its ability to protect us from the disease.
On September 15, 2020, researchers from the Government Institute of Medical Sciences, Greater Noida, and the Institute of Genomics and Integrative Biology (IGIB), New Delhi, uploaded a preprint paper confirming two cases of reinfection from India. The patients – a 25-year-old male and a 28-year-old female, both healthcare workers in the Noida hospital – got infected with a different variant of the virus the second time, about three and a half months after their first infection. The next day, the IGIB team also confirmed reinfection in four Mumbai healthcare workers, although the report is yet to appear online.
The healthcare workers from Noida had more viral particles than when they got infected the first time, although they remained asymptomatic. The researchers also noted that the viral strain they were reinfected with contained a mutation that wasn’t present earlier, and which allowed the virus to resist neutralising antibodies – the kind of antibodies that prevent the virus’s entry into the body.
The viral genome
This is probably the first report of asymptomatic infection and reinfection, and it calls for better surveillance.
“As a significantly large number of people who are infected are asymptomatic, without surveillance, we would never be able to estimate the real numbers of infection. Therefore, surveillance of healthcare workers, who are at higher risk than the population, would be something really worth considering,” Vinod Scaria, a senior scientist of genome informatics at IGIB and one of the authors of the study, told The Wire Science.
Upasana Ray, a senior scientist of infectious diseases and immunology at the Indian Institute of Chemical Biology, Kolkata, agreed that long-term patient monitoring is important irrespective of the symptoms. She added that more gene-sequencing data should help us identify and understand the type of virus in circulation, and understand when a new ‘variant’ shows up.
Sequencing the virus’s genome also helps distinguish between reinfection, where the virus enters the body a second time and infects the person, and reactivation, where the virus remains in an inactive state in the body and later becomes active again.
Epidemiologists had speculated on the possibility of reactivation and reinfection of the virus even in April, when about 51 patients in South Korea who had been ‘cured’ of the disease tested positive again. South Korea’s Centers for Disease Control and Prevention initially proposed that they were cases of reactivation of the virus. But upon further research, they announced that the test results were all false positives: the test kit had detected remnants of the virus that were not infectious.
Other researchers reported the first formal case of reinfection on August 24, 2020, when a 33-year-old man from Hong Kong tested positive for the SARS-CoV-2 virus about four and a half months after the first infection. The reinfection, however, was less severe and the patient was asymptomatic.
One way to confirm reinfection is to test whether viral strains from the two infections are different. This is useful because as the virus mutates, different strains of the virus circulate in different regions at different times. In the Hong Kong case, scientists confirmed that the viral strain involved in the reinfection was different from the first infection. In fact, the reinfection strain was most closely related to a strain circulating in Europe around July-August, where the patient had travelled at the time. The study was published on August 25 in the journal Clinical Infectious Diseases.
Another case of reinfection has been reported from Nevada, in the US, where – unlike the Hong Kong case – the symptoms were worse when a 25-year-old man contracted the virus a second time. The authors of the preprint paper confirmed this to be a case of reinfection as five nucleotides present at specific places of the viral RNA from the first infection were different in the viral RNA from the second infection.
That said, the authors also considered another possibility: that the virus from the first infection evolved into a different type inside the body. If that were true, this would be the fastest rate of the virus evolving inside a person – nearly four times as fast as is known now.
Mind the rarity
These cases raise many questions. For example, are reinfections frequent or rare? Do subsequent infections evoke milder symptoms or worse? Can those who have been infected the second time spread the virus while remaining asymptomatic? And how do reinfections change the prospects of a vaccine?
In a press conference held on September 15, Balaram Bhargava, director-general of the Indian Council of Medical Research, said that although COVID-19 reinfections are possible, they are “very, very rare”, and added that it’s not a matter of serious concern.
The preprint paper in the Nevada case noted that the frequency of reinfection can’t be defined by a single case study. However, we shouldn’t grow complacent, its authors implied, as they said we just be limited by our ability to detect reinfection: “The lack of comprehensive genomic sequencing of positive cases in the US and worldwide limits the sophistication of public health surveillance required to find these cases,” they wrote.
Although experts say it is too early now to comment on the frequency of reinfections, many think that it’s possible. “The likelihood of someone getting a second infection after 4 months is not huge at all but after a year, we don’t know as yet,” Gagandeep Kang, a professor at Christian Medical College, Vellore, had said in a previous interview with The Wire.
Indeed, a study published in July this year reported that reinfections with some human coronaviruses, which cause mild respiratory illnesses, could occur within the same year.
“We show that reinfections by natural infection occur for all four seasonal coronaviruses, suggesting that it is a common feature for all human coronaviruses, including SARS-CoV-2,” another paper published a few days ago said. “Reinfections occurred most frequently at 12 months after infection, indicating that protective immunity is only short-lived.”
As discussions around the confirmed cases of reinfection from Hong Kong, Europe and the US have played out, some experts also took to Twitter to explain that such rare events of reinfection have precedence in some viral infections like influenza and measles. And since we have successful vaccines against these illnesses, they said that we have no need to panic.
Lots of recent discussion about #SARSCoV2 re-infections, with 2 pre-prints describing possible examples. To contextualize these re-infections, I’d like to discuss the following papers, which document same-season re-infection with influenza, and re-infection with measles (1/6).
— Bloom Lab (@jbloom_lab) August 28, 2020
Immunologists have wondered about the role immune cells play in remembering the first infection and protecting the patient from succumbing to reinfection. If the person is asymptomatic or has a milder infection the second time, it means the immune system is responding as it should. This leads to another question: do reinfected patients who are asymptomatic continue shedding the virus, thus infecting others around them? Because if they do, they put the susceptible population – especially those who can’t be vaccinated – at greater risk of infection.
“Since reinfection can occur, herd immunity by natural infection is unlikely to eliminate SARS-CoV-2,” Akiko Iwasaki, a professor of immunobiology at the Yale School of Medicine, tweeted on August 24. “The only safe and effective way to achieve herd immunity is through vaccination.”
A first case of #COVID19 reinfection from HKU, with distinct virus genome sequences in 1st and 2nd infection (142 days apart). Kudos to the scientists for this study.
This is no cause for alarm – this is a textbook example of how immunity should work.
— Prof. Akiko Iwasaki (@VirusesImmunity) August 24, 2020
Implications for vaccines
Therefore, reinfection has implications for vaccine development – although it doesn’t rule out the role of a vaccine in providing protection, Ray said. If COVID-19 reinfections are common, it would imply that vaccines might not completely protect against the virus. Instead, we might have to design and use seasonal shots – like with the flu – as a new ‘variant’ of the virus takes over from an older one in the population.
And these seasonal shots could also vary from country to country, considering reinfection data indicates different countries may harbour different variants of the virus in the same season. This would also mean that even those who have been infected with the virus would have to get vaccinated to protect themselves from reinfections.
Ray also said choosing the antigen – the component of the virus used in the vaccine to prepare our immune system – is key. “Where reinfection is an issue, careful mutation studies are required,” Ray said. Analysing the virus’s genome could help us understand which parts of proteins in the virus haven’t changed much. And researchers could use these so called ‘conserved immunodominant areas’ to make vaccines, she added.
The array of symptoms that people with COVID-19 have reported also has a part to play in this context. For one, the variety has prompted experts to consider how our immune system remembers the virus’s first infection and fight it during subsequent infections. Studies have shown that asymptomatic patients have fewer antibodies against the virus and that the duration for which a person is protected from the virus may be short. Further, not everyone has high levels of neutralising antibodies.
Some experts are also asking whether antibodies produced against the virus may help, instead of fight, a different strain of the virus during reinfection. This phenomenon, called antibody dependent enhancement, interfered with efforts to find vaccines for other coronaviruses, including the ones that cause SARS and MERS.
“Data from the study of SARS-CoV [the virus that causes SARS] and other respiratory viruses suggest that anti-SARS-CoV-2 antibodies could exacerbate COVID-19 through antibody-dependent enhancement,” the authors of a paper published on September 9 wrote.
We also need to understand the genetic factors that may influence the risk of reinfection. “In my opinion,” Scaria said, “the most important questions would be why some people develop recurrent infections and how the host and pathogen genetic factors influence this.”
But while experts grapple with these questions, they have also held steadfast to their recommendations: continue masking, practice physical distancing and wash your hands as often as you can – even if you contracted the virus and recovered.
Joel P. Joseph is a science writer.