Association between natural immunity and risk of SARS-CoV-2 reinfection and COVID-19 hospitalization


Study: Risk of SARS-CoV-2 reinfection and COVID-19 hospitalisation in individuals with natural and hybrid immunity: a retrospective, total population cohort study in Sweden. Image Credit: joshimerbin/Shutterstock

Against the background of the ongoing coronavirus disease 2019 (COVID-19) pandemic, with high vaccine coverage in several regions coupled with increasing rates of new infections in some hotspots, a new Swedish study examines the protective effect of immunity engendered by natural infection in contrast to hybrid immunity.


There has been much controversy over whether individuals who have a history of prior COVID-19 need to be vaccinated against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Such individuals generally show an immune response to the administration of a COVID-19 vaccine, indicating that vaccination continues to be beneficial.

However, pending hard evidence, the task of persuading those with prior infection to take a primary series of the vaccine, plus boosters, is made more difficult. With vaccine passports becoming a requirement in some places, considerable differences have been revealed in the approach to issuing such passports. Should those with prior infection be recognized as immune or only those with hybrid immunity?

The current study, which appears in The Lancet Infectious Diseases, aimed to shed light on this issue.

What did the study show?

The study used Swedish national registers maintained by three different entities to form three cohorts. The first comprised unvaccinated people with natural immunity, and unvaccinated infection-naïve individuals, of the same sex and age. The second and third cohorts included those who had taken one or two doses of the vaccine after a prior infection, again matched by age and sex to those with prior infection but unvaccinated.

The investigators looked for evidence of SARS-CoV-2 infection and hospitalization for COVID-19 over a period from March 20th, 2020, until October 4th, 2021, and September 5th, 2021, respectively. However, follow-up was shorter in cohorts 2 and 3, which were enrolled later, and during a period of lower infections.

Over the follow-up period of 164 days, non-immune individuals had over 99,000 documented infections, with approximately 2,000 hospitalizations. Conversely, those with natural immunity developed 34,000 infections, with approximately 3,200 hospitalizations. The risk of infection after natural infection was 95% lower. In comparison, the risk of hospitalization in this group was initially higher for the first three months but was reduced by 87% over the next 20 months.

The risk was higher among the older age groups and those born out of Sweden as well as those with higher education.

During a follow-up of 52 days, after a single dose of vaccine, following prior infection, the risk was reduced by 58% for reinfection, compared to those with natural immunity alone, in cohort 2. The effect weakened thereafter. It was also weaker in older people and those who had other illnesses.

There were eight hospitalizations in the one-dose hybrid immunity group, vs. 110 in the natural immunity group, for a reduction of 44%.

After two doses in previously infected individuals, there were just over 400 reinfections, with six hospitalizations, compared to 800 cases and 40 hospitalizations in those with natural immunity alone.

Two-dose hybrid immunity reduced reinfection risk by 56% compared to natural immunity, lasting at least nine months. The number of people with natural immunity who need to take two doses of vaccine in order to prevent one reinfection is 767.

What are the implications?

Overall, in those with prior infection, both one and two doses of vaccine were associated with a reduced risk of either reinfection or hospitalization than natural immunity alone. In the natural immunity cohort, the risk of reinfection was low for the next 20 months or more but reduced further with vaccination for the next nine months.

It is important to note that the difference in the number of cases and of hospitalizations in the natural immunity and hybrid immunity cohort is small, especially in the latter. Thus, there remains little evidence to promote the need for vaccination in those previously infected, especially with the long duration of immunity in this study, for 20 months or more.

Natural immunity seems to be of longer duration than vaccine-induced immunity, corroborating an Israeli study that recently published early findings and an earlier study by the same authors who showed waning vaccine effectiveness in Sweden within a few months. Nonetheless, hybrid immunity showed better protection against hospitalization than natural immunity, but the small numbers in this scenario call for further studies.

These findings suggest that if passports are used for societal restrictions, they should acknowledge either a previous infection or vaccination as proof of immunity, as opposed to vaccination only.”

This is of special relevance in regions that have been poorly covered by vaccination, especially since the current Omicron variant possesses impressive vaccine-antibody escape characteristics.

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