SARS-CoV-2 anti-nucleocapsid antibodies reduce risk of reinfection for at least eight months

As the coronavirus disease 2019 (COVID-19) pandemic continues to take a heavy toll on the world population, scientists are seeking to identify the protective impact of prior infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Study: Impact of baseline SARS-CoV-2 antibody status on syndromic surveillance and the risk of subsequent COVID-19—a prospective multicenter cohort study. Image Credit: visuals21/ ShutterstockStudy: Impact of baseline SARS-CoV-2 antibody status on syndromic surveillance and the risk of subsequent COVID-19—a prospective multicenter cohort study. Image Credit: visuals21/ Shutterstock

A new study published in the journal BMC Medicine concludes that at least with predominantly wild-type variants, the risk of reinfection with the virus among unvaccinated people is reduced by 80% or more.


The induction of immunity against SARS-CoV-2 infection by natural infection or vaccination protects against subsequent infection. The centrality of this to the successful containment of this virus has led to multiple studies exploring the magnitude and duration of protection against reinfection, especially that specific antibodies offer.

More reinfection cases are being reported with a mean interval of over 100 days between the first and second infection. Nonetheless, many researchers have shown the presence of neutralizing antibodies against the virus for nine months or more and their ability to block reinfection.

Especially important is one UK study that included 12,000 healthcare workers (HCW) monitored for six months, which showed a lower risk of having virus in their nasopharyngeal swabs. The current study, published in the journal BMC Medicine, looks at both reinfection rates and COVID-19-specific symptoms among the participants based on the baseline detection of anti-nucleocapsid antibodies.

What did the study show?

The researchers conducted the study in Switzerland, in approximately 4,800 HCW. The participants were followed up for almost eight months.

The results show that the presence of specific antibodies to the nucleocapsid antigen of the virus is correlated with protection against a positive nasopharyngeal swab (NPS) later, as well as with the occurrence of COVID-19-specific symptoms like anosmia and muscle pain.

At baseline, 3% of the participants, or 144, had antibodies to the virus.

All participants were followed up by symptom diaries at about 24 questionnaires (median) until vaccination, which comes to 0.71 diaries per person per week. Over 5,300 swabs were carried out, with almost two-thirds being tested by polymerase chain reaction and the rest by antigen tests. This covered over 2,700 individuals, called the NPS group.

Both tests showed comparable accuracy, but the mean number of swabs was lower among seropositive individuals vs. seronegative, at 47% and 57%, respectively. At least one swab tested positive during the follow-up period in 550 participants. Only three of these came from the 67 seropositive individuals in the group.

In contrast, of the 2,645 seronegative participants, there were 547 positives, making up over one-fifth of the group. All three were detected in January 2021, at about six months from the baseline positive antibody test. One of them, who had the highest anti-spike antibody titer, had an asymptomatic infection.

The relative risk (RR) of testing positive for the virus by NPS is thus 78% less for seropositive individuals. When the full cohort is included in the analysis, the RR is still lower, at 72% below that of seronegative individuals.

The timing of the infection suggests that they were infected when the Alpha variant made up less than a fifth of all isolates, and the Delta virus was largely absent from the picture. Other studies have shown that immunity to prior strains is less than 80% after natural infection vs. vaccine-induced immunity. Further research will show how long vaccine immunity lasts compared to that induced by infection.  

Symptom surveillance

Of the total. 60% of HCWs had one or more symptoms over the follow-up period, including 60% of those who were seronegative at baseline and 55% of the seropositive subset. This means that the symptom number was comparable in both groups.

Interestingly, three out of fifteen symptoms were found to be less common in the seropositive group. The RR of anosmia or dysgeusia was reduced by 66%, while chills were 40% less common and pain in the limbs or muscles 32% less frequent.

Most symptoms (14/15) were less frequent in those who tested positive compared to the negative NPS group. The greatest specific predictive power was thus associated with changes in taste/smell, weakness, and limb or muscle pain.

Those with dysgeusia/anosmia were at 22 times higher risk of testing positive, while the other two symptom sets were linked to a 4.4-4.7 times higher risk.

What are the implications?

The results underline the protective effect of anti-SARS-CoV-2-specific antibodies against infection. Earlier studies showed a 90% reduction in infections among seropositive individuals compared to seronegative at three to six months.

Another study suggested that while 80% of people with antibodies at baseline were protected against infection at six months, the efficacy waned to 47% in the elderly (65 years or above). The risk reduction by 78% in the current study matches these earlier findings.

By using seropositivity rather than confirmed infection as the baseline, the risk of missing seropositive cases because of lack of testing was avoided. The current study shows that the NPS testing rate is lower among the seropositive group.

While both groups showed an equal number of symptoms over the follow-up period, discriminative symptoms such as muscle pain and sensory changes were less common among the seropositive group, confirming that these individuals had a reduced risk of infection.

Some symptoms may have been reported by seropositive patients, such as anosmia, which tends to persist for weeks in a few patients. If all seropositive participants with such symptoms had been excluded from the analysis, the discriminative power of this symptom might have been even higher.

Newer variants of the virus are emerging, which can break through the immune defenses erected by the host against the ancestral strains. Recently, scientists have reported severe COVID-19 occurring due to reinfection with a novel variant in an immunocompetent individual who had anti-nucleocapsid antibodies at baseline. This agrees with the finding of reinfection in three nurse assistants with anti-spike antibodies at the time of the test.

The use of anti-nucleocapsid antibodies may have led to missing a few cases since anti-spike antibodies are more largely neutralizing. However, using these antibodies helps distinguish infection from vaccination since the titers of both anti-N and anti-S antibodies were observed to be equal. The protective effect of anti-S antibodies maybe even higher than that offered by anti-N antibodies.  

Cellular immunity was also not measured, which may have contributed to underestimating the true efficacy of seropositivity on subsequent infection rates. This may be offset by the reduced sensitivity of antigen tests used in over a third of the swabs.

We conclude that anti-nucleocapsid antibodies acquired after natural infection convey an approximately 80% protection against symptomatic SARS-CoV-2 infection, at least for a period of 8 months.” The participants came from an unvaccinated setting without the newer variants."

Finally, they observed the utility of symptom surveillance, commenting,

Syndromic surveillance for specific COVID-19 symptoms allows estimating the probability of SARS-CoV-2 reinfection irrespective of whether participants undergo NPS testing or not.”

Journal reference:
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.


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