COVID-19 Reinfection—The Sky is not Falling

“The most important question for reinfection, with the most serious implications for controlling the pandemic, is whether reinfected people can transmit the virus to others.” Angela Rasmussen, Columbia University, virologist

“Everyone seems to have gone ‘Argh.’ But we don’t know what level of antibodies are needed for protection.” Katie Doores, Kings College London, biochemist

Since the beginning of this pandemic, one of the burning questions for scientists (and one that’s captured the public’s attention as well) has been, “Can those with a history of COVID-19 be reinfected?” Following four recent reports of reinfections, the answer is now in: “Yes.” The goal of this Germ Gem post is to discuss what we’ve learned from these cases as well as the implications for vaccine-induced protection and for the course of the pandemic itself. But before describing these reinfection cases, a definition of some terms may be helpful.

Infection v. reinfection. An “infection,” as defined by many infectious diseases specialists, refers to “an established relationship between a microbe and a host.” If the host (e.g., a human) is provoked by the relationship, it is then called an “infectious disease.” The disease can be manifested by symptoms of illness or it can be asymptomatic and only detected by laboratory tests, as with development of antibodies. While the absence of illness is good news for the individual host, nonetheless asymptomatic individuals can transmit microbes to others. (In the case of COVID-19, for example, asymptomatic people account for about 40% of viral transmission).

A “reinfection” refers to a recurrent (another or subsequent) episode of the same infection caused by the same pathogen. In COVID-19 reinfections, the culprit remains the coronavirus SARS-CoV-2, but it is a changed or evolved strain of the virus. In the four cases of COVID-19 reinfection described below, it is such viral mutants (detected by molecular testing of the genes [genome] of SARS-CoV-2) that is causing concern. As described in a September 8 News Feature in Nature“The coronavirus is mutating—does it matter?”, researchers are carefully tracking coronavirus mutations around the globe, and (not surprisingly) they still have more questions than answers.

Cases of COVID-19 reinfection. The first case of confirmed COVID-19 reinfection was in a 33-year-old man in Hong Kong. He was originally diagnosed with COVID-19 on March 26. He was hospitalized and recovered. In August, upon returning to Hong Kong from Spain via the United States, reentry screening at the Hong Kong airport detected SARS-CoV-2. Whole genome sequencing found the first viral isolate (i.e., the one that caused infection on March 26) was most closely related to SARS-COV-2 strains from the U.S. or England, and the second viral genome was most closely related to strains from Switzerland and England. Of note, he was asymptomatic during the course of the reinfection by SARS-CoV-2 (yet this doesn’t mean he was not able to spread the virus).

The second and third cases of COVID-19 reinfection were diagnosed in Belgium and the Netherlands. They followed a similar scenario to the Hong Kong case. The Belgian patient was a woman who had a relatively mild illness in March and then another episode again in June. The Dutch patient was an older person with a weakened immune system who developed mild disease with both infections. Genetic testing of the viruses in both cases showed that the SARS-CoV-2 strains causing their second infections were different than their first isolates, confirming that these were reinfections. Fortunately, the illnesses associated with their first and second infections (that is, reinfections) were mild.

None of these three reinfections triggered much alarm. In fact, they suggested that the immune system was doing its job—protecting the patients from developing severe disease when they became reinfected. The fourth case of reinfection, however, caused more concern.

The report of the fourth case, published online, describes a 25-year-old healthy man living in Reno, Nevada who tested positive for SARS-CoV-2 in April after showing mild illness. He totally recovered, but then became ill again in late May. Unlike the three patients with reinfection described above, the second time around, this fourth patient developed more severe COVID-19 requiring hospitalization. Genetic testing showed that his two bouts of COVID-19 were caused by distinct strains of SARS-CoV-2.

Why are these cases of COVID-19 reinfection important? These four cases demonstrate that immunity to reinfection can’t be expected in all cases of COVID-19. This dashed the hope of some experts that the novel coronavirus SARS-CoV-2 might behave more like its cousins SARS-CoV-1, the cause of severe acute respiratory syndrome (SARS), and MERS-CoV, the cause of Middle East respiratory syndrome (MERS), both of which produce immunity lasting at least several years after infection. Nonetheless, most experts agree that this isn’t a “the sky is falling” moment in the COVID-19 pandemic. After all, there are more than 26 million infections worldwide to date and there appears to be a very small number of reinfections overall.

Lessons to be learned from immunity to other coronaviruses. There are more than 100 different kinds of viruses that cause the common cold (which is not necessarily a trivial viral infection). Three different strains of coronavirus are among them. These coronaviruses have received much less research attention than those causing SARS, MERS, or COVID-19. But, they are responsible for many days of lost work and productivity. Therefore, in the late 1980s, the Common Cold Unit of the UK’s Medical Research Council in Salisbury, England studied the immune response to the coronaviruses that cause common colds.

In one such study, 15 healthy people were quarantined and monitored for symptoms for three weeks after snorting a nostrilful of solution containing a coronavirus. About a year later, 14 of the volunteers returned to do it again. The second time, while they showed no symptoms associated with the common cold (i.e., were asymptomatic), analyses of their blood revealed that nearly all of them became infected before their immune systems could launch an effective defense. Thus, they all had an asymptomatic reinfection.

Taken together with the evidence so far with COVID-19, it appears that an initial infection with SARS-CoV-2 usually confers immunity to symptomatic reinfection. Nonetheless, the reinfection of the patient in Reno, Nevada does raise the question, “Will COVID-19 be like the flu?” In the case of influenza, the virus mutates to such a degree that new strains emerge each year requiring annual adjustment of the vaccine. But experts all agree that it’s way too early to tell for sure how long protection will last with any of the SARS-CoV-2 vaccines that are currently on the launching pad for release within the next six months.

Reasons for optimism. I find it absolutely astonishing that as of September 2, the global COVID-19 vaccine research and development landscape includes 321 vaccine candidates, and of these, 32 are in clinical trials. Seven of the candidate vaccines that are in clinical trials are supported by the US Operation Warp Speed program, which aims to deliver 300 million vaccine doses for COVID-19 by January 2021.

Proceeding at a similar record pace as vaccine development is the research enterprise aimed at understanding the mechanisms involved in immunity to SARS-CoV-2. On September 1, in a News Feature in the medical journal Nature, it was suggested by the immunologists digging deeply into the virus, “the data are so far unsurprising—and that bodes well.” Mehul Sutha, a viral immunologist at Emory University is quoted as saying, “We’re seeing great immune responses and fantastic looking antibodies. We just don’t know the longevity of that response yet. Unfortunately, that will take time.”

Studies of the immune response to SARS-CoV2 include not only those focused on neutralizing antibodies and long-lived memory B lymphocytes (i.e., white blood cells that secrete antibodies), but also on T cells (i.e., a specific type of lymphocyte that plays a central role in the immune response), including T cells that recognize other coronaviruses that can cross-react to SARS-CoV-2. The lessons learned so far give reason to be optimistic that immunity to SARS-CoV-2 will be lasting. Also, while it’s too early to be sure, virology experts believe SARS-CoV-2 doesn’t mutate as rapidly as influenza viruses.

The road to elimination of SARS-CoV-2. To date, only one human pathogen has been “eradicated” (defined by the World Health Organization [WHO] as “a complete and permanent worldwide reduction to zero new cases of an infectious disease through deliberate efforts with no further control measure required”) from the face of the Earth—variola major—the cause of smallpox. But, many pathogens have been controlled or “eliminated”(defined by the WHO as a “reduction to zero (or a very low defined target rate) of new cases in a geographical area as a result of deliberate efforts”). Notable examples are polio and measles. (Polio is very close to being eradicated and measles eradication is primarily impeded by anti-vaxxers.)

It is unlikely that COVID-19 is going to be eliminated anytime soon. But, successful containment strategies eliminated the transmission of one of the coronaviruses, SARS-CoV-1 (the last case of SARS was reported in 2004). This can be accomplished again. With appropriate containment strategies and one or more vaccines, I’m confident the elimination of COVID-19 is an achievable goal.