2 major takeaways from the first confirmed case of Covid-19 reinfection

"We may be seeing more of this."

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Can you get coronavirus twice? Though there were some earlier reports suggesting it could happen, most were false alarms — situations likely triggered by false positives.

However, on Monday, researchers presented the first confirmed case of coronavirus reinfection documented so far.

In a study forthcoming in the journal Clinical Infectious Diseases, scientists at the University of Hong Kong describe the case of a 33-year old man who is now in otherwise good health. In March, the patient was hospitalized with Covid-19, but cleared the infection and was discharged.

Four and a half months after he was first diagnosed with coronavirus, he tested positive again in an airport upon returning to Hong Kong after a trip to Spain.

The Hong Kong case has two main takeaways:

  1. We may be seeing more cases like these as the pandemic continues.
  2. The patient appeared to show no symptoms upon reinfection, a further sign that the immune system can mount a strong response to the virus the first time around.

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Cynthia Derdeyn is a professor at the Emory Vaccine Center. She tells Inverse that the findings are probably not a fluke.

Using genetic analysis, the team showed that this individual was infected with two distinct genetic strains of SARS-CoV-2, which means that his positive result is unlikely due to testing errors or the fact that some people can continue to shed viral RNA (not necessarily infectious virus) for months. Derdeyn describes the results as "pretty compelling." She was not a part of the team behind this case study.

"For people who got infected early on in the pandemic, it looks like there's maybe this four or five-month window where reinfection can happen," Derdeyn says. "We may be seeing more of this." On Tuesday, a Belgium broadcaster reported another case of reinfection, however, the results have not been published in a journal.

Editor's note 8/28/20: A new case of reinfection was detected in Nevada, according to a pre-print study (not peer-reviewed) posted on August 27 and submitted to The Lancet. Unlike the Hong Kong patient, this patient did show symptoms upon reinfection.

In April 2020, a 25-year old tested positive for coronavirus. The patient had symptoms like cough, fever, diarrhea, headache, and nausea. By the end of April, symptoms dissipated and the patient tested negative. The patient felt fine until May 31, when they sought care for headache, fevers, cough, nausea, and diarrhea. The patient later went to the hospital on June 5, where they were confirmed positive for Covid-19 again. The authors argue that genetic information "virtually assures" that this is a case of reinfection.

In a tweet, Akiko Iwasaki, an immunologist at Yale University explained that the case calls for further examination of how reinfection could lead to a range of outcomes. "As more and more reinfection cases will be reported, we should get a better sense of how well the immune system after natural infection protects against disease," she said.

Lauren Rodda, a post-doctoral fellow in the University of Washington's Department of Immunology, agrees that this research demonstrates that the patient was infected with two variants of SARS-CoV-2. The findings also update our understanding of what "immunity" really means: It's less about not getting the virus again, and more about faring better should reinfection happen.

"Being 'immune' to a virus, does not mean a person will not get re-exposed and reinfected," Rodda tells Inverse. "They will, but the infection will be controlled much more quickly without causing symptoms and likely without being contagious."

What does coronavirus reinfection really mean?

The question at the heart of this story is how antibodies (y-shaped proteins produced by the immune system) actually stop a SARS-CoV-2 contribute to immunity.

What we know so far comes from studies of vaccines, which help the body produce antibodies without first getting the virus and case studies based on people who naturally encountered SARS-CoV-2.

Vaccine research suggests that the body can mount a strong immune response to SARS-CoV-2, or at least pieces of the virus. Numerous vaccine candidates have proved that they're capable of training the body to produce neutralizing antibodies – the type of antibody that can, in theory, stop SARS-CoV-2 from entering cells.

A case report posted last week on the pre-print server MedRXiv does suggest antibodies can prevent infection and illness. When coronavirus struck aboard a fishing trawler from Seattle, 104 out of 122 members of the crew tested positive for the novel coronavirus. Three crew members actually had neutralizing antibodies before they got on the vessel — none of these passengers fell ill.

Now, we have a case of reinfection that complicates the picture. A person becoming reinfected with Covid-19 doesn't undermine the fact that antibodies do offer protection, it just redefines how we think about that protection.

As Yale immunologist Akiko Iwasaki noted in a tweet on Monday, that this individual showed no symptoms the second time around. They also had no detectable antibodies when they were reinfected, she points out.

However, the case study authors point out that a smaller "residual" low level of antibody may have helped temper the second infection. Antibodies aren't the only markers of immunity, but they are the only ones reported in the study.

"His immune response prevented the disease from getting worse," she told The New York Times.

Derdeyn adds that getting infected a second time "may be not as worrisome."

Meanwhile, Rodda goes so far as to say that it's the sign that the immune system is really doing its job. The first time someone is infected, the immune system has to devise a reaction from scratch. The second time around, things should go more smoothly.

"The immune system has kept some of the best SARS-CoV-2 fighters around and their experience means they can fight off the virus much faster which translates to fewer or, better yet, no symptoms," Rodda adds.

Can 'reinfected' people infect others?

While reinfection might actually be a sign of a robust immune response, it's unclear whether a reinfected person could actually go on to transmit the virus. That's a concern, especially for those in high-risk groups who are at risk of becoming infected for the first time.

The case study team didn't recover infectious virus from this individual and didn't test to see whether that virus could then infect another cell. In turn, it can't prove that reinfected individuals can spread the virus. However, Derdeyn says that she thinks it's possible.

"I think the fact that they could find it and sequence it suggests that it is replicating and it could be transmitted."

Rodda cautions against that conclusion. It's possible that an infection that's controlled quickly by the immune system means that the virus has less time and resources to replicate or go on and infect someone else. Right now, we don't know which way things will break.

"There is no data in this paper or presented by others yet about whether a reinfected person is contagious and this is an overreach in their conclusions," she says.

What does this case mean for the future?– This is a sign that getting the virus once doesn't mean you get a get-out-of-jail-free card.

But it's not all bad news, Derdeyn says. It points us in the direction of new questions we'll have to address to make a better vaccine.

She notes that there was a significant genetic distance between the strain of SARS-CoV-2 that infected this individual the first time and that that infected him the second time. "If you're infected, and that immunity doesn't protect you from another infection you really need to understand why that is and try to address that with a vaccine," she says.

Rodda adds that there are promising signs that the immune system is wise to this genetically-disparate type of virus too. If viruses are different enough, it might allow them to evade the immune system. In this case, that didn't happen, suggesting that "the immune response had the breadth to deal with this level of genetic changes to the virus," she says.

At the moment, we're just dealing with one case study, but it's pointing scientists in many new directions, and perhaps rethinking how we look at immunity for the time being – we may expect lesser disease, but reinfection is possible.

As more of these cases emerge — and both experts say they will — that picture may get even clearer.

Background: Waning immunity occurs in patients who have recovered from COVID-19. However, it remains unclear whether true re-infection occurs.
Methods: Whole genome sequencing was performed directly on respiratory specimens collected during two episodes of COVID-19 in a patient. Comparative genome analysis was conducted to differentiate re-infection from persistent viral shedding. Laboratory results, including RT-PCR Ct values and serum SARS-CoV-2 IgG, were analyzed.
Results: The second episode of asymptomatic infection occurred 142 days after the first symptomatic episode in an apparently immunocompetent patient. During the second episode, there was serological evidence of elevated C-reactive protein and SARS-CoV-2 IgG seroconversion. Viral genomes from first and second episodes belong to different clades/lineages. Compared to viral genomes in GISAID, the first virus genome has a stop codon at position 64 of orf8 leading to a truncation of 58 amino acids, and was phylogenetically closely related to strains collected in March/April 2020, while the second virus genome was closely related to strains collected in July/August 2020. Another 23 nucleotide and 13 amino acid differences located in 9 different proteins, including positions of B and T cell epitopes, were found between viruses from the first and second episodes.
Conclusions: Epidemiological, clinical, serological and genomic analyses confirmed that the patient had re-infection instead of persistent viral shedding from first infection. Our results suggest SARS-CoV-2 may continue to circulate among the human populations despite herd immunity due to natural infection or vaccination. Further studies of patients with re-infection will shed light on protective correlates important for vaccine design.

Editor’s note: A previous version of this article mistakenly stated that the patient had mild symptoms upon reinfection. He showed no symptoms.

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