What the N501Y Coronavirus Reinfection Means for the Pandemic


Addressing concerns on viral immune evasion, disease severity on reinfection, and antibody and vaccine efficacy.


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The first proven coronavirus reinfection occurred in August 2020, where a 33-year-old man got reinfected with a different SARS-CoV-2 variant or strain with the D614G mutation. The detection of two distinct SARS-CoV-2 strains rules out the possibility of viral reactivation or persistence that may be caused by the same initial virus.

Soon, more reports of reinfections emerged, nearly all of which were due to the D614G mutation. Now, with the advent of N501Y mutation in the U.K. and South Africa, which has spread to over 20 more countries, more reinfection cases can be expected. In fact, the first one has already happened.

The first reinfection from N501Y mutation

The details are published in a paper titled “Confirmed Reinfection with SARS-CoV-2 Variant VOC-202012/01” in the Clinical Infectious Diseases journal a few days ago. VOC-202012/01 means variant of concern-2020 December/#1. It also goes by other names: VUI-202012/01, B.1.1.7 lineage, or 20B/501Y.V1. Nonetheless, they are all defined by the N501Y mutation that increases viral infectivity and transmissibility, but not virulence.

In the paper, researchers at the Barts Health NHS Trust in London described a 78-year-old man with a history of multiple comorbidities — such as type 2 diabetes, chronic obstructive pulmonary disease, and ischaemic heart disease — who got Covid-19 during the first pandemic wave in April 2020. The disease was mild, and he recovered with ease.

Since the man has diabetic neuropathy, he is a hemodialysis patient who undergoes routine SARS-CoV-2 testing. He was tested negative for SARS-CoV-2 RNA — indicative of no virus shedding — from 5th May to 1st December 2020. His antibodies for SARS-CoV-2 nucleocapsid protein were positive, at least until 13th November 2020.

“Antibody reactivity to nucleocapsid protein indicates previous exposure to SARS-CoV-2 but not whether antibodies that can block infection (anti-spike) are present.”

However, he was tested positive for SARS-CoV-2 RNA on 8th and 14th December 2020. He was then admitted to the hospital with shortness of breath that started three days prior. His breathing symptom worsened overnight. He can’t talk and had severe hypoxia requiring intubation. He developed severe Covid-19 pneumonia with heart complications and was admitted to the intensive therapy unit (ITU).

The researchers then sequenced the SARS-CoV-2 genomes from the man’s clinical samples collected on 2nd April and 8th December 2020. In contrast to the first infection, the newer SARS-CoV-2 that caused the reinfection had 18 amino acid changes in the entire genome, of which 7 occurred in the spike protein that include the D614G and N501Y mutations.

“The WGS [whole genome sequencing] results confirm reinfection with a different lineage 8 months after initial infection in the absence of significant immunocompromised,” the authors concluded. “The reinfection was with the ‘new variant’ VOC202012/01.”

What the N501Y reinfection means for the pandemic

1. Immune evasion?

“Anti-SARS-CoV-2 antibodies were still present shortly before onset of reinfection, with no evidence of antibody waning,” the authors wrote. “This may raise some concerns about immune evasion by this new variant, which is a concern with the high number of spike region mutations seen.”

However, a pre-print study has found that antibodies isolated from persons vaccinated with the Pfizer-BioNTech mRNA vaccine for Covid-19 were equally effective at neutralizing SARS-CoV-2 with or without the N501Y mutation.

Furthermore, the D614G and N501Y mutations that increase the SARS-CoV-2 infectivity and transmissibility also promote an ‘open’ state of the virus’s spike protein. However, this ‘open’ state also makes the coronavirus more vulnerable to antibody binding and neutralization. More details are found here: Why the Coronavirus D614G and N501Y Mutations Are Not Entirely Disastrous

So, it’s unlikely that the N501Y strain evaded the immune system, as the authors have suspected. In fact, the study tests for antibodies against the SARS-CoV-2 nucleocapsid protein, not the spike protein. “Antibody reactivity to nucleocapsid protein indicates previous exposure to SARS-CoV-2 but not whether antibodies that can block infection (anti-spike) are present,” wrote Akiko Iwasaki, an immunology professor at Yale University known for her massive scientific contribution to Covid-19.

Vaccines can be designed to elicit the most appropriate and effective immune responses than natural infections could.

2. Worse disease?

The 78-year-old man also caught a more severe and life-threatening Covid-19 on his reinfection. But this is unlikely due to the N501Y mutation, as existing evidence did not find that N501Y increases the virus’s virulence in humans.

Indeed, more severe reinfections from SARS-CoV-2 without the N501Y mutation have happened before. But this may be an unfair comparison as “the reinfection cases in general are being picked up because of symptoms and are biased towards detection of symptomatic cases,” Prof. Iwasaki stated.

“Asymptomatic reinfection cases can only be picked up by routine community testing…and we are probably severely underestimating the number of asymptomatic reinfections,” she continued. Indeed, most reinfection cases have resulted in milder Covid-19. Thus, the man’s reinfection case may be an outlier.

Plus, there’re uncontrolled variables in his case. The viral dose on second exposure and whether the man’s health worsened over the past few months from the multiple medical comorbidities are unknown. We also know that old age, male sex, and comorbidities are the leading risk factors for more severe Covid-19. So, it’s not unexpected that severe Covid-19 happened to the man this time.

3. Will the vaccine still work?

The short answer is yes. As mentioned, antibodies isolated from vaccinated persons could neutralize SARS-CoV-2 with the N501Y mutation, at least in cultured cells in the lab.

Also, in theory, vaccine-induced immunity is often stronger and more specific than naturally acquired immunity. Indeed, a person’s immune system might not mount robust immune responses if the infection is too mild. This is why vaccination is key to herd immunity. Vaccines can be designed to elicit the most appropriate and effective immune responses than natural infections could.

In Covid-19, for example, the vaccines are designed to target the SARS-CoV-2 spike protein rather than the nucleocapsid protein. “The protection given by the [human papillomavirus] jab, for instance, is more durable and better than natural infection,” said Charlotte Houldcroft, Ph.D., a virologist at the University of Cambridge. So, vaccines are still imperative at minimizing the risk of N501Y reinfection.

Short abstract

Covid-19 reinfections happened before when the D614G mutation emerged a few months ago. Presently, with the newer arrival of the N501Y mutation, we can expect more reinfections. Indeed, the first case has already happened to a 78-year-old man in London. This article then discusses what the N501Y reinfection means for the pandemic, answering key questions about the virus’s immune evasion ability, antibody effectiveness, disease severity upon reinfection, and vaccine efficacy.

Jan 2021 update: We are also now seeing more reinfections from another SARS-CoV-2 mutant with the E484K mutation: The ‘Most Worrying’ Coronavirus E484K Mutant Has Arrived

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