EXPERT REACTION: First reported case of COVID-19 reinfection

With the case of COVID-19 reinfection from Hong Kong, which is being widely reported, the sequencing confirmed that the person has been infected by two genetically different strains of the virus. Different from previous reports that may have been related to prolonged infections, this case indicates that immunity wasn’t long-lasting and re-infection and renewed viral shedding occurred within four months. Somewhat reassuringly, the re-infection was asymptomatic, indicating that some clinical immunity may have remained.

This isn’t altogether unsurprising, as we know that immunity to seasonal coronavirus – which are the cause of the common cold – isn’t long lasting either. The four-month time of reinfection also coincides with a point where the varieties of anti-SARS-CoV-2 antibodies have decreased very significantly. Therefore, it is likely COVID-19 isn’t a disease like measles, where you can develop life-long immunity. How long COVID-19 immunity really lasts and how this immunity differs between severe, mild and asymptomatic, remains unclear.

We are investigating this at the Walter and Eliza Hall Institute, to determine how long immunity against coronavirus lasts, in a research study called COVID PROFILE. We suspect immunity against the disease may be no longer that a year or two. Through regular, detailed investigation of the immune responses throughout the course of a year after people have recovered, COVID-PROFILE seeks to understand how immunity is acquired, how long immunity can last and why exposure to the virus may not provide long-lasting protection.

This will not only help to better understand and predict the future of the global pandemic but will also impact the development and use of future vaccines. If vaccine-induced immunity is similar to natural immunity, then it is possible that a vaccine might not provide life-long immunity, and repeated vaccinations against the virus, every couple of years, may be required.

If we can predict the way immunity to the virus develops over time, whether people can be reinfected, and whether symptoms are less severe upon reinfection, we will be able to plan accordingly and stay ahead of the virus.

I think this is a perfect example of the thinking that isn’t happening regarding COVID vaccines. There seems to be an expectation on the part of many in the media that a 'successful' COVID vaccine will only be one that is 100 percent effective at eliminating COVID infection and transmission and rewinds the clock to October 2019.

A more realistic expectation would be a vaccine, which prevents you getting sick on re-exposure to COVID-19, including different strains, and reduces, but probably doesn’t eliminate, your propensity to transmit infection to others. We’ve seen increasing examples of this happening with measles vaccine as reported from Victoria in 2019 and California a bit earlier. There we saw infection with much milder symptoms occurring in people who received two doses but some time ago and occasionally may transmit to others.

If this young man's recent symptomatic infection turned his recent exposure into an an asymptomatic infection, then great. In the current environment however, not knowing his capacity to transmit (function of viral load and nature of contact) and not being able to protect potential vulnerable contacts by vaccines, pre or therapeutics post exposure to him, then he has to be treated exactly the same as someone with no history of vaccination or infection - quarantined etc. Whither immunity passports?

Some viral infections are known to generate life-long immune responses, such as measles, while others will only provide limited immunity for few months, such as the common cold and the flu viruses. As COVID-19 infections are new in humans, we do not know much about the nature of immune responses against SARS-CoV2. It was hoped that this virus will generate long lasting immune responses like its close relatives, the SARS and MERS viruses, but it seems to be different.

This current re-infection case highlights two main issues in my opinion. The first, is the importance of vaccination and probably the need of multiple doses to generate the desired antibody level that can protect us from infection. Or for a vaccination system similar to the flu vaccination, when each year a new selection of active variants of the virus are included.

The second issue is that the 33 years old man had some symptoms in the first infection, but antibodies were not detected after recovery, yet in the second infection antibodies against the virus were detected and he was asymptomatic. Usually immune responses in second infections are generated from the activation of B and T memory cells, which will act against the viral antigen and generate an army of antibodies to fight the infection.

This patient was infected with a slightly different strain of the virus in the second time, but his immune response were capable of balancing the viral load and keeping it under control, as it did not develop to the symptomatic stage.

This may make us think if this is a reason behind the mystery cases that are driving community infections in Victoria, for example, as recovered individuals may get infected for a second time and spread the virus without noticing any symptoms. Therefore, PCR testing of asymptomatic individuals in hot spot areas and probably screening for immune responses in recovered patients may contribute to further knowledge on this.

The occurrence of reinfection by SARS-CoV-2 in a 33-year-old man from Hong Kong is helpful in some ways, but also leaves a number of unanswered questions. Trying to determine if reinfection with SARS-CoV-2 was possible on the basis of antibody levels in blood and other markers of immunity was always an exercise in speculation. The only way to prove this was to see if someone actually became reinfected; now that it has happened, we definitely know that reinfection with SARS-CoV-2 can occur. It is also pleasing to see that the second infection was associated with an antibody response and with no illness, suggesting that subsequent infections can be associated with a more robust immune response and a milder illness.

Of the limitations, we don't know if he was infectious to others. Secondly, the fact that this occurred after such a short period between infections is disappointing. Also, this was only one case; therefore, we don't know how common or rare reinfection is. This apparently is a young and healthy man: will the second illness be as mild in an older person or someone with a chronic disease? This man had a mild first illness: will someone with a more severe illness have a more durable immune response that means reinfection won't occur for over a year? Could cross-immunity to other coronaviruses modify the risk of reinfection? Certainly, this case of reinfection is an important discovery but there is still much to be discovered.

A key question in the COVID-19 pandemic has been whether we can be re-infected with the virus after recovering. There have been anecdotal reports of people getting infected twice, but what hasn’t been clear is whether they really cleared the virus the first time round and got infected again, or whether they never really cleared the virus in the first place.

A study published yesterday from Hong Kong showed definitively that a 33-year-old man was re-infected. They established this by sequencing the virus isolated from his first positive test, and comparing that viral genetic sequence to his second positive test (approx. 4 and half months later). Importantly, during the second infection, the man showed no symptoms. This is how we expect immunity to work: even if we can get re-infected, our immune system is able to respond quickly enough because of its existing antibodies and T cells so that we don’t get sick.

Even though the man showed no symptoms, he was still infectious – meaning he could still transmit the virus, which means that herd immunity through natural infection may not be the best approach. Vaccines are designed to mimic that first natural infection, but we expect and hope that they will protect us from getting symptoms and from transmitting the virus. More widespread studies are needed to establish how common this re-infection is and how it affects people of different age groups and risk factors.

The finding that a person in Hong Kong has been confirmed to be reinfected with SARS-CoV-2 is not unexpected. Recent published work on people naturally infected with the virus have shown their antibody levels start to fall soon after and 20 per cent of people infected have baseline antibody levels after two months. This is how our normal common cold coronavirus strain behaves and is why we are continually infected with them year after year. 

These two findings mean that any country who is relying on natural herd immunity as a way to deal with COVID-19 is on the wrong path as this will not be effective. Going forward what we need to know is how long T cell immunity lasts in naturally infected people and more importantly how long vaccine responses last as this will determine how often we need to be vaccinated

The finding that a person was re-infected with a different strain of COVID-19 reminds us yet again not to get ahead of ourselves, not to be complacent, and recognize we are still learning about the pathology of this virus.

In terms of policy, it underscores the need for continuing strict preventative measures until an effective vaccine is available and widely distributed.  Counting on 'herd immunity', to the extent it was ever a good strategy, is now seriously called in to question.

It also should give pause as to the effectiveness of vaccines. We will need to develop vaccines that are effective against all global strains of the virus and ensure extended antibody and cellular immunity. This will be especially important for those with compromised immune systems, such as the elderly or individuals with co-morbidities.

On the one had this sounds quite frightening; after all who wants to be infected with SARS-CoV-2 once, let alone infected twice. However, it is perfectly logical that this would occur with a respiratory virus. Even when we develop immunity it doesn’t mean that we will not have an infection, it generally means that the infection is less severe.

The question not being explored at this stage is why? Was the person not following public health instructions, do they have a high risk occupation, a genetic susceptibility or is this just bad luck? In this case, the second infection was asymptomatic, which some people will interpret as good news as this indicates that vaccinations should be a useful public health intervention. 

The PCR test is extremely sensitive and will pick up a very low level of viral RNA in the upper respiratory tract. My perception has always been that we get low-level replication and boosting in influenza in those who are successfully vaccinated. In fact, I doubt whether any vaccine will give permanent, absolute protection against reinfection in the upper respiratory tract or mouth for a virus that comes in via those routes, and the same may be true of natural infection. The report says that the second time around, the person was asymptomatic and we don’t know if he would have replicated enough virus to cause further spread.

Measles, for example, infects via the mouth and nose where it first replicates in epithelial cells in those mucosal sites. To stop that we need sufficiently high levels of protective IgG and/or IgA (antibodies) in those sites. But it causes disease by systemic spread by the blood to the skin, brain, lung, inner ear etc. The levels of antibody in blood are generally sufficient to stop that happening. In the early days of measles vaccination, giving only one shot of the vaccine proved to be insufficient as the levels of infection fell in the community, indicating that vaccinated kids were being boosted by mild, localised infection. As a consequence, they went to a second shot of vaccine.

The recent case of reinfection isn’t surprising, and is in agreement with already existing information regarding how long the immune response lasts post-infection.

Although this is an important case, much more data is required for us to understand the implications of reinfection.

Critical questions are; To what extent people who are reinfected, shed virus? Secondly, people who have been reinfected with COVID, how symptomatic are they, and are the symptoms better or worse than previous infections?

We would hope that people who are reinfected, don't shed as much virus, and having contracted the virus a second time, doesn't result in as severe an illness compared with the first time. Time will tell.

There have been reports of reinfection from early in the pandemic but investigations in the past, such as in South Korea, have shown that many of these may have been persistent viral shedding in people who recovered clinically, and also shedding of non-infectious viral fragments after recovery.  However, we do know re-infection is possible with other coronaviruses because immunity is not long-lasting, so it may also be possible with SARS-CoV-2. The body of evidence to date also suggests that people with an asymptomatic or mild infection may not mount a strong antibody response.

In this case, reported prior to publication (the paper is scheduled to be published in Clinical Infectious Diseases), a man in Hong Kong who had a mild case of COVID-19 in March was reinfected with a genetically different strain of SARS-CoV-2 in August. The fact it was a genetically distinct strain, and the long time lag between the first and second infection are strong evidence of reinfection. The first time, he did not develop antibodies. So, this tells us reinfection is possible, especially in people who have mild infection and do not develop antibodies. Other research also suggests that asymptomatic or mild infections may not result in a robust antibody response. This may also explain why serological surveys of young children show low rates of infection - not because they are not getting infected, but because they are infected, have mild infection and are not developing antibodies. This means that vaccines for COVID-19 should produce a strong antibody response to make sure people can fight off infection.

We do not really know the extent of the SARS-CoV-2 reinfection problem for many reasons. The fact that it can happen at all a few months after 'recovery' is disturbing, as it has possible implications for vaccine development.

There is nothing simple about this disease. The SARS-CoV-2 virus infection presents in many different forms, including of course the well-recognised and potentially life-threatening respiratory version. But many people appear asymptomatic, are mildly affected, or have other manifestations of the disease, including new onset diabetes, heart, brain/stroke liver, gut, skin and kidney problems. Some of those can be difficult to spot and the true proportions of the population affected is still hard to assess.

Reinfection probably does occur, but it is still difficult to know exactly how often this happens with current testing levels, but so far it seems to be a rare event. The problem is further complicated by the concurrent circulation of several SARS-CoV-2 viral strains with different levels of infectivity and severity, each with possible variable manifestations and complications.

We are still lacking data, but there is no intrinsic reason to think that immunity to one strain of the coronavirus confers immunity to infection by another strain (influenza is the perfect example where we need to develop new flu vaccines regularly to cope with strain variation). Again, we don't know if this will be a problem for SARS-CoV-2 because we are yet to produce a proven effective vaccine. The fact is that antibodies and cell-mediated immunity have complex and variable individual patterns, which means that some people may lose immunity quite quickly and others won't. It is not safe to make assumptions about the properties of this virus, we are on a steep learning curve to try and understand the deep biology of the disease. Despite the massive ongoing international scientific efforts to investigate COVID-19, it is still going to take time to figure it all out.

We should be careful in interpreting too much out of a single case of reinfection, however, it is the first lab-confirmed case of reinfection that we know of. This case is interesting because the person had a mild infection the first time and remained asymptomatic the second time. The virus that caused the infection the second time appears to be completely different from the original virus. Interestingly there were no detectable antibody responses after the first infection, however, a boosting of antibody response was seen after the second infection.

I would look at the positive side of the story. He was asymptomatic and there was a boosting of his antibody responses. This tells us that immunity can be enhanced by reinfection and that could potentially mitigate the severity of the disease when we get it the second time. This is good news for vaccine development and this is what we would expect vaccines to do.