Reinfection in COVID-19 – part one

Setting it Straight - Issue #23

Written by Nobel Laureate Professor Peter Doherty

Among the most frequently asked questions regarding immunity to the SARS-CoV-2 virus that causes COVID-19 is: how long does protection last? So far, that question has been raised mainly because people are wondering if they can contract this infection a second time. But, as vaccines are rolled out, there will be the added issue of vaccine efficacy and durability if, as seems likely, the virus continues to circulate at some level or other after widespread immunisation. As you go through what follows in the next essay or two, you might come to the conclusion that, whether or not you have had COVID-19, a regular vaccine boost could be a good idea.

Those who have been concerned about reinfection point to frequent instances where people who test positive, then negative, for SARS-CoV-2 subsequently test positive again. Is that evidence of reinfection, or of viral genome (see Back to basics essay) persistence at low levels? The way to distinguish between those two possibilities is to exploit the small mutations (changes in viral RNA) that can emerge as SARS-CoV-2 replicates itself to identify different sub-strains by gene sequencing. Though the coronaviruses mutate at much lower levels than we see some other viruses (influenza, HIV) that use RNA as their information system, SARS-CoV-2 mutational ‘bar codes’ can be used both to track the sub-strains that are circulating in different geographical regions, and to test where the one individual has been infected sequentially with two distinct viruses. Now, we have clear evidence that at least one healthy, younger person has indeed been infected twice with different SARS-CoV-2 strains.

A report from the University of Hong Kong laboratory of leading virologist K-Y Yuen and his associated clinical colleagues details how a 33-year-old local man in good health who presented with coughing, fever and headaches was hospitalised after testing positive by the standard PCR (polymerase chain reaction) test for viral genome from a swab taken at the back of the mouth (oropharynx). Though he wasn’t all that ill, Hong Kong has been very aggressive re admitting COVID-19 patients and has an outstanding record of keeping the disease in check. He was discharged two weeks later after testing negative twice by PCR.

Returning from a trip to Spain and the UK 142 days later, he again tested positive when screened at Hong Kong Airport and was hospitalised for observation. His levels of virus detected in saliva quickly declined and, sequencing the PCR product obtained from the first and second episodes, showed that the two viruses were from distinct, known sub-strains. Clearly, he had been reinfected while in Europe. Serum antibody testing at 10 days after the first diagnosis and a day after the second was negative, though he became seropositive on day five. That rapid seroconversion indicates that his immune response was indeed primed by the first infection, but that the levels of SARS-CoV-2 spike protein-specific IgG generated initially were too low to persist in the blood (see Essays over the past weeks). Remaining asymptomatic through the second incident, there were minimal signs from other tests that he was in any way clinically compromised.

So, should this ring every alarm bell about the possibility that, even if we have been infected and/or vaccinated, we are still at risk of developing clinical COVID-19 disease? The first thing that we should realise is that this pandemic is, with the rapid advances in medical technology, being monitored at a level that is unprecedented in the history of human infectious disease. That’s illustrated by the fact that, the second time round, he was tested automatically by PCR after getting off an international flight at Hong Kong Airport. No such screening was done during the 2002/3 SARS-CoV-1 outbreak with, as you may recall if you were travelling at that time, the only check being for increased body temperature or other obvious clinical signs. Being unaware that he had been reinfected, our Hong Kong patient would have just walked on through the airport.

The idea that mild reinfection will provide a natural ‘booster shot’ that leads to better, long-term immunity is, in fact, very familiar. There’s a very good example of that from the early days of measles vaccines. Like SARS-CoV-2, measles virus invades by infecting cells in the nose/mouth region, principally in the oropharynx. The virus particles (virions) produced at that initial site of infection then get into the blood (viremia) and disseminate to the skin (the characteristic spots), middle ear, lung, brain and so forth. Though we have perfectly good vaccines, measles still kills more than 140,000 people a year, mainly unvaccinated children in the poorer countries.

The current, live attenuated measles vaccine that multiplies a little bit in the oropharynx was rolled out from 1968 as a ‘one shot’ protection strategy. Then, in 1981, the USA started to again experience measles outbreaks. It turned out that children maintained their immunity while there was still enough measles virus circulating in the community to give them a mild reinfection. Once transmission fell off, though, the clinical disease returned. The problem was solved by giving a second shot of the vaccine. No matter how successful any vaccine may be, this is what we could well be looking at with COVID-19. Next week, we’ll unpick the issue of reinfection in more (hopefully accessible) scientific detail.