Study Confirms First US Case Of COVID-19 Reinfection, Indicating Exposure May Not Translate To Total

• First study to confirm COVID-19 reinfection in US, fifth confirmation of reinfection worldwide
• Verified 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
• Findings indicate that exposure to COVID-19 may not translate to guaranteed total immunity, but further research of reinfection cases is required

In the first study to confirm a case of COVID-19 reinfection in the US, researchers found evidence that an individual with no known immune disorders or underlying conditions was infected with SARS-CoV-2 in two separate occurrences. According to a new case study published in The Lancet Infectious Diseases journal, the patient, a 25-year old male living in Washoe County, NV, was infected with two distinct SARS-CoV-2 variants within a 48-day timeframe, while testing negative in between infections. The patient’s second infection was more severe, resulting in hospitalization with oxygen support, indicating previous exposure to COVID-19 may not translate to guaranteed total immunity, but that further research into reinfections is required. The authors note that all individuals—whether previously diagnosed or not—should take identical precautions to prevent infection with SARS-CoV-2.

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After testing positive for SARS-CoV-2 in April 2020, the patient tested negative for the virus on two separate occasions. In June 2020, after experiencing severe COVID-19 symptoms, including fever, headache, dizziness, cough, nausea, and diarrhea, the patient was hospitalized and tested positive for a second time. The patient has since been discharged from the hospital and has recovered from the second infection. A full timeline is available in the paper.

“There are still many unknowns about SARS-CoV-2 infections and the immune system’s response, but our findings signal that a previous SARS-CoV-2 infection may not necessarily protect against future infection,” said Mark Pandori, PhD, of the Nevada State Public Health Laboratory, located at the University of Nevada, Reno School of Medicine and lead author of the study. “It is important to note this is a singular finding and does not provide generalizability of this phenomenon. While more research is needed, the possibility of reinfections could have significant implications for our understanding of COVID-19 immunity, especially in the absence of an effective vaccine. It also strongly suggests that individuals who have tested positive for SARS-CoV-2 should continue to take serious precautions when it comes to the virus, including social distancing, wearing face masks, and handwashing.”

The genomes of the patient’s virus samples were sequenced in April and June, displaying significant genetic differences between the two cases, implying the patient was infected twice by two distinct SARS-CoV-2 infections.

At least four other reinfection cases have been confirmed globally in Belgium, the Netherlands, Hong Kong, and Ecuador. However, only the Ecuador reinfection case displayed worse disease outcomes than the first infection.

“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,” Dr. Pandori said. “So far, we’ve only seen a handful of reinfection 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 reinfection.”

Similar to observations with the reinfection case in Ecuador, the 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. The authors present several hypotheses to potentially explain the severity of the second infection, including the possibility the patient subsequently encountered a very high dose of the virus which caused a more acute reaction the second time. The patient may also have come in contact with a more virulent version of the virus. Another 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 has been seen previously with the SARS-CoV betacoronavirus as well as other diseases, such as dengue fever.

Furthermore, the authors explain there is a very slim possibility of a continuous infection involving some form of deactivation/reactivation. However, for such a hypothesis to be true would require a mutational rate of SARS-CoV-2 that has not currently been observed. Finally, another alternative 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.

The authors acknowledge a limitation of the study is that they were unable 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 (eg, neutralizing antibody titers) during the second episode.

It is also important to note that this case and other confirmed reinfection cases occurred among patients who displayed COVID-19 symptoms, meaning there is the possibility that many infections and/or reinfections 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 US 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,” Dr. Pandori said.

In a linked commentary, Akiko Iwasaki, PhD, a professor of Immunobiology and Molecular, Cellular and Developmental Biology at Yale University, US, who was not involved in the study, explores what is known about the current confirmed cases of reinfection, and the possible implications for public health and vaccinations. She said: “as more cases of reinfection 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.”

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