Confirmed early re-infection with SARS-CoV-2

By Dr. Liji Thomas, MDSep 22 2020

As scientists strive to develop commercially viable and effective antivirals and vaccines to counter the growing COVID-19 pandemic, there is considerable uncertainty about how long and how durable the immunity induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is. A new paper recently published in the journal Clinical Infectious Disease in September 2020 reports a confirmed case of re-infection with this virus following recovery.

Transmission electron micrograph of SARS-CoV-2 virus particles, isolated from a patient. Image captured and color-enhanced at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID

Re-infection: The Early Evidence

The earliest report of a patient who had recovered from COVID-19 but again tested positive for the virus was the starting point for much discussion and research on whether the infection indeed induced lasting immunity against re-infection, like many other viral illnesses. A second talking point was whether re-infection if it happened, could lead to severe COVID-19 just like the original infection.

As far back as April 2020, about 50 patients in South Korea were reported to have tested positive after having been declared to have recovered and discharged home. Initially, it was felt that they were cases of reactivation. A second hypothesis was that the test kits had produced false-positive results by picking up viral remnants rather than whole infectious virions.

In August 2020, however, an irrefutable case of re-infection occurred, when a Hong Kong man tested positive some four and a half months from the first infection. This episode was remarkable in that the re-infection was less severe, producing none of the COVID-19 symptoms. The reinfecting strain was different from the original strain, confirming that this was no reactivation.

Another case report from Nevada suggested that all re-infections need not follow this pattern, with the patient developing more severe symptoms the second time around. This time, too, the second infection occurred with another strain than that which caused the first infection.

A third and more alarming possibility would be that the virus inside the patient’s body had mutated to a new strain, which would mark a fourfold jump in the known rate of viral mutation if confirmed.

Questions Raised by Reinfections

While only a handful of true re-infections have been reported worldwide, this does raise many questions about whether all patients develop neutralizing antibodies, and if so, how long do they last? How does this impact the prospects of universal COVID-19 vaccination? How often can re-infections be expected to occur? And do re-infected asymptomatic patients continue to shed the virus, thus serving as unsuspected reservoirs of infection?

Other researchers have pointed out that with the known seasonal coronaviruses, re-infections naturally occur quite commonly, typically at about a year, indicating transient protective immunity.

Healthy Young Male Develops Re-infection

Against this background, the current paper reports a case of re-infection that occurred within just 90 days of the original SARS-CoV-2 infection. The patient was in the military medical corps, a 42-year-old male who developed cough, fever, and muscle aches at the end of the third week of March 2020. He reported workplace exposure to the virus, and a reverse transcriptase-polymerase chain reaction (RT PCR) was negative. The illness resolved by the tenth day, and his health was excellent, as before infection, for the next 51 days.

At this point, he again developed fever, dyspnea and gut symptoms after having been exposed to a case of COVID-19 in his household. The symptoms were noticeably worse than those of the first infection. Radiologic signs were positive for pulmonary infiltration, as was the RT PCR test for SARS-CoV-2. The serum sample obtained from him a week after the onset of the second episode showed the presence of IgG antibodies to the viral spike protein.

The researchers attempted to culture the virus unsuccessfully, but RNA sequencing was done, generating a SARS-CoV-2 genome. The genome sequence from the first infection was built using some fragments of viral RNA amounting to just over 4,000 base pairs, with the rest being sequenced from the second illness.

Phylogenetic analysis showed this virus had the lineage B.1.26, and it encoded the D614G spike protein mutation associated with increased infectivity. When the two sequences were compared, the researchers discovered multiple potential variations, of which at least one was associated with a high confidence level.

Implications

The researchers point out that this patient was a young male with robust immunological function, but with a more severe clinical course in the second infection. This raises the question of whether this could have been due to antibody-dependent enhancement (ADE), a phenomenon in which non-neutralizing antibodies help a different strain of the virus to infect host cells rather than hinder viral infection. This was seen with the earlier SARS and MERS outbreaks.

Other possible reasons for the re-infection include exposure to a more pathogenic strain or a higher dose of the virus during the second exposure within the household. And since both strains were non-identical, this means that immunologists need to identify conserved viral antigens, which do not undergo significant mutation, to develop a vaccine against COVID-19.

The study concludes, “The clinical, epidemiological, and sequencing data of this case suggest early re-infection with SARS-CoV-2, only 51 days after resolution of initial infection.”  This will add to the knowledge base about the possibility of re-infection with this virus, and reinforce the need for surveillance, especially of healthcare workers who are not only more likely to be exposed to the virus but may be involved in its transmission in healthcare settings, as well.