The Mutations that Caused Covid-19 Reinfection Explained

And what does it mean for our natural or artificial (vaccination) immunity? [Updated September]

Shin Jie Yong
Aug 28 · 8 min read
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Health photo created by freepik — www.freepik.com

Recent headlines declared the world’s first proven case of Covid-19 reinfection in Hong Kong. It is said as proven because researchers showed that a different strain of SARS-CoV-2 caused the second infection, rather than the initial virus that persists in the body.

On the same day, coincidentally, there are two other reports of Covid-19 reinfections — an elderly in the Netherlands and a middle-aged woman in Belgium — but their details are lacking. Recurrent positive RT-PCR tests for SARS-CoV-2 occurs at about 10% of the time, which may also be due to reinfections, false positive, persistent infection, or lingering viral fragments.

So, there may have already been more than one reinfection event. The big question is what do Covid-19 reinfections mean for our immunity? Note that immunity can be acquired naturally (via recovery from the disease) or artificially (via vaccines).

Key aspects of the research paper detailing the Covid-19 reinfection case

The Hong Kong case is described in a paper, titled “COVID-19 reinfection by a phylogenetically distinct SARS-coronavirus-2 strain confirmed by whole genome sequencing,” that was accepted into the journal Clinical Infectious Diseases on 25 August.

A 33-year-old man contracted Covid-19 for the second time 142 days after the first symptomatic Covid-19 infection. He was hospitalized on 29 March and recovered and discharged on 14 April upon two consecutive negative RT-PCR tests. On 14 August 2020, he was tested positive for Covid-19 again upon his return to Hong Kong airport from Spain via the U.K.

Although he did not develop any symptoms upon reinfection, his immune system made a new bunch of antibodies and proinflammatory cytokines. Whether the man is contagious or not is uncertain; isolating and culturing viruses in cells to check infectivity is an experiment that would take some time to complete.

This suggests that the A222V and D614G mutations are likely responsible for changes in the virus’s biological features or immunogenicity.

Fortunately, viral genomic data are available for both the first and second infections. Researchers then found out that a different strain of SARS-CoV-2 caused the reinfection (see figure below). “Whole-genome analysis showed that the SARS-CoV-2 strains from the first and second episode belong to different clades/lineages with 24 nucleotide differences,” the authors wrote, “suggesting that the virus strain detected in the second episode is completely different from the strain found in the first episode.”

(Strain means a variant with distinct biological properties. A variant means any forms of a virus with different genomic sequences, which may or may not result in a new biological function.)

“For our patient, there are four amino acid residues that differ in the spike protein between the first and second infection, including L18F, A222V, D614G, and Q780E,” the authors added. Among these, “A222V and D614G may affect the structure of these [viral spike protein] epitopes.” This suggests that the A222V and D614G mutations are likely responsible for changes in the virus’s biological features or immunogenicity.

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Source: Wang et al. (2020). Figure: Phylogenetic analysis of whole SARS-CoV-2 genomes showing the relationship between the two strains of the patient.

More on the mutations that caused the reinfection

There is scarce scientific data about the A222V mutation, where the amino acid at position 222 changed from A (alanine) to V (valine). Computational analyses predict that the A222V mutation occurs in one of the viral spike proteins that T-cells target. Other than that, no functional studies have been done with A222V-mutated SARS-CoV-2. In contrast, the D614G mutation has been studied extensively.

Covid-19 reinfections raise two concerns…“The first is that it suggests that previous infection is not protective. The second is that it raises the possibility that vaccinations may not provide the hope that we have been waiting for.”

The D614G mutation changed the amino acid at position 614 from D (aspartic acid) to G (glycine). This shifts the original D614 to the new G614 strain. Thus, as evident in the figure above, the D614 strain caused the first infection, and the G614 strain (plus a few other mutations) caused the reinfection.

The G614 strain now constitutes at least 75% of all circulating SARS-CoV-2 as of July. It is infamous for its 10-fold increase in infectivity in cultured human cells, which may or may not reflect actual viral transmission among humans. For more information on what implications do different strains of SARS-CoV-2 bring, kindly see the link below.

These Covid-19 reinfections raise two concerns, said Dr. David Strain, a senior clinical lecturer at the University of Exeter and co-chair of the British Medical Association’s medical academic staff committee. “The first is that it suggests that previous infection is not protective. The second is that it raises the possibility that vaccinations may not provide the hope that we have been waiting for.” How much of a threat these two concerns pose?

Concern 1: Natural infection

Natural infection means that a person builds immunity following recovery from the disease. And we now know that natural Covid-19 infections do not always guarantee permanent immunity. But scientists are not so surprised. The common cold caused by endemic coronaviruses, for example, can strike the same person more than once, even within the same season.

Notably, a second natural infection (or reinfection) usually results in milder disease. “It is quite likely that subsequent infections do not cause as severe an illness as the first episode because of some degree of residual immunity, which may not be sufficient to stop the infection but [may] be enough to reduce the risk of severe illness,” explained Paul Hunter, a professor of medicine at the University of East Anglia, and a fellow of the Royal College of Pathologists, Biology, and the Faculty of Public Health.

And, indeed, the man in Hong Kong and woman in Belgium did not develop any symptoms upon reinfection. “Even though [the patient] got infected with a very different strain that’s distinct from the first time around, they were protected from disease,” Mark K. Slifka, a virologist professor at the Oregon Health and Science University, commented. “That is good news.”

If the man had stronger immune reactions during the first infection, reinfection might not have happened. And vaccines can be designed to elicit the best and most robust immune responses against a particular infection.

All of these suggest that some degree of immunity persists despite waning antibodies. This is because the adaptive immune system — that remembers pathogens and confers immunity — consists of B-cells and T-cells. B-cells make antibodies to neutralize the infection, killer T-cells kill infected cells, and helper T-cells enhance activities of other immune cells (including B-cells).

Concern 2: Vaccination

In the Hong Kong reinfection case, the man only had a mild Covid-19 on his first infection. A mild disease generally means immune responses that are less powerful. Indeed, the man’s immune system did not generate high levels of antibodies on the first infection, which researchers think may have made him susceptible to subsequent reinfections.

Put it another way; it also means that if the man had stronger immune reactions during the first infection, reinfection might not have happened. And vaccines can be designed to elicit the best and most robust immune responses against a particular infection. “You can aim at inducing protection that would be better than what you would get from an infection,” said Nicolas Vabret, an assistant professor of medicine who specializes in immunology. “The protection given by the [human papillomavirus] jab, for instance, is more durable and better than natural infection,” agreed Charlotte Houldcroft, a virologist at the University of Cambridge.

“The D614G mutation is therefore unlikely to have a major impact on the efficacy of vaccines currently in the pipeline, some of which exclusively target the RBD.”

Second, a vaccine does not have to be 100% effective. As long as vaccines help increase herd immunity, where people immune to the virus help to slow the spread of disease, cross-protection can be achieved. An immune person is a dead-end for the virus, after all. “Any type of herd immunity is better than zero,” said Walter A. Orenstein, a professor of medicine, epidemiology, global health, and pediatrics at Emory University and former director of the U.S. National Immunization Program. “Increasing the number of immune people in the population, even for a little while, is still going to result in breaks in the transmission chain and reduce the chances more people will get ill.”

Lastly, recalled that the A222V and D614G mutations best explain the Covid-19 reinfection case in Hong Kong. While data on the A222V mutation is lacking, at least the D614G mutation does not change the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. The RBD is what binds to the ACE2 receptor of mammalian cells. “The D614G mutation is therefore unlikely to have a major impact on the efficacy of vaccines currently in the pipeline,” explained a July review in Cell. A new genomics study published in PNAS on 29 August, titled “A SARS-CoV-2 vaccine candidate would likely match all currently circulating variants,” also found no evidence of mutations affecting the RBD of SARS-CoV-2.

Short Abstract

Researchers have finally confirmed a Covid-19 reinfection case in Hong Kong, which is caused by a different strain of SARS-CoV-2 that differed from the first by four mutations. Two of these mutations (A222V and D614G) best explain the changes in biological properties and immunogenicity of the virus. While data on the A222V mutation is scarce, at least the D614G mutation does not affect the primary viral structure that vaccines target.

Covid-19 reinfection raised concerns about immunity obtained naturally or by vaccinations. While natural infection may not ensure full immunity, a second exposure generally results in a milder disease owing to residual immunity. And vaccines can be designed to generate immune memory that is better than natural infections and, thus, may prevent reinfection. Even if vaccines do not prevent reinfection, they still help increase herd immunity.

September update: A study published in Clinical Infectious Disease recorded the second case of Covid-19 reinfection in a 42-year-old healthy male in the U.S. A different strain of SARS-CoV-2 with the D614G mutation caused the reinfection. But this second infection produced a more severe disease for unclear reasons. Explanations include immune misfiring or greater viral inoculum.

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