The Lancet Infectious Diseases: Vaccines provide extra protection for those with immunity from a previous COVID-19 infection, according to two new studies

• Two new studies confirm that COVID-19 vaccination provides significant additional protection among people who have already been infected with SARS-CoV-2, especially against severe disease.
• As populations increasingly include individuals with both vaccination- and infection-driven immunity, studies that offer insights into the protection associated with different forms of immunity can help inform global vaccine strategies.
• However, further research is needed to understand the impact of new variants, including omicron, and its ability to evade immunity.
• Two new studies published in The Lancet Infectious Diseases journal confirm that COVID-19 vaccines provide additional protection for people who have already been infected with SARS-CoV-2, especially against severe disease.

In the first study, conducted in Brazil, researchers found that four vaccines – CoronaVac, Oxford-AstraZeneca (ChAdOx1), Janssen (Ad26.COV2.S) and Pfizer-BioNTech (BNT162b2) – provide additional protection against symptomatic reinfection and severe outcomes – such as hospitalisation and death – in people who have already had a SARS-CoV-2 infection. The study did not include cases of reinfection from the omicron variants.

A second study, conducted in Sweden, found that the first three months following SARS-CoV-2 infection were associated with higher mortality compared to non-infected individuals but patients who survived and recovered were then at a lower risk of re-infection for up to 20 months. In addition, vaccination against COVID-19 provided additional protection to those with a previous infection for at least nine months. However, importantly, the study only followed people up to October 2021, so did not include any analysis of reinfection from the omicron variants.

Previous research has shown that COVID-19 vaccines are effective at preventing infection and hospitalisation in those without a previous infection. Together, the studies provide important information on vaccine effectiveness in individuals with a prior infection as well as other forms of immunity against COVID-19, helping to inform global vaccine strategies.

Vaccines offer additional protection for those with infection-driven immunity

In the first study, researchers aimed to determine whether the four COVID-19 vaccines licenced for use in Brazil – CoronaVac, Oxford-AstraZeneca (ChAdOx1), Janssen (Ad26.COV2.S) and Pfizer-BioNTech (BNT162b2) – offered additional protection against symptomatic infection, hospitalisation and death, to those reinfected with SARS-CoV-2.

“COVID-19 vaccines have been proven to be highly effective at preventing symptomatic infection and hospitalisation among those with no prior infection but effectiveness for those with prior infection is less clear. Understanding the duration and effectiveness of immunity for those vaccinated with a previous COVID-19 diagnosis becomes increasingly important as the pandemic progresses and surges in new cases may occur as a result of more transmissible variants. Further research on the need for vaccination for those with a previous COVID-19 infection is a vital step to pandemic policy intervention including guidance on single dose or two dose vaccine protection,” says study author Julio Croda, Universidade Federal de Mato Grosso do Sul and Fundação. [1]

Participants were selected from national disease surveillance and vaccination databases if they had a PCR confirmed SARS-CoV-2 reinfection, at least 90 days after they contracted the initial infection [2] (22,566 people in total). The primary outcomes analysed were symptomatic COVID-19 and hospitalisation or death within 28 days of the positive test categorised by vaccination status.

Among people who had experienced a SARS-CoV-2 infection and were later vaccinated, vaccine effectiveness against symptomatic reinfection was 39% for CoronaVac, 56% for Oxford-AstraZeneca, 44% for Janssen, and 65% for Pfizer-BioNTech. Effectiveness against hospitalisation and death was 81% for CoronaVac, 90% for Oxford-AstraZeneca, 58% for Janssen, and 90% for Pfizer-BioNTech. Of the 22,566 reinfection cases recorded, 1,545 people were hospitalised and 290 people died within 28 days of a positive test. Past studies suggest that the level of protection after COVID-19 infection varies among individuals, however there is increasing evidence that vaccination following infection further increases protection against subsequent illness among those who have been previously infected. [3]

“All four of these vaccines have proven to provide significant extra protection for those with a previous COVID-19 infection, reducing hospitalisation and death. There has been ongoing public debate about whether previously infected individuals need to be vaccinated. Our results suggest that vaccine benefits far outweigh any potential risk and support the case for vaccination, including the full vaccine series, among individuals with prior SARS-CoV-2 infection,” says Croda. [1]

The authors acknowledge some limitations with this study. Firstly, vaccine effectiveness was unable to be classified by age group [4]. The differences in the timing of participants receiving vaccines according to their eligibility (more vulnerable groups were given priority in the vaccine rollout) also mean that comparison of the effectiveness of different vaccines should be taken with caution. Only tests performed at least 90 days after the initial infection were considered in this study. In addition, no individual-level data were available for different variants of COVID-19 and therefore variant-specific vaccine effectiveness cannot be determined.

Writing in a linked Comment, Pramod Kumar Garg, Translational Health Science and Technology Institute, India, who was not involved in the study, says: “The results of Cerqueira-Silva’s study and other recent studies challenge the concept of population-level herd immunity through natural infection alone against SARS-CoV-2 and suggest that vaccinating individuals who were previously infected provides further protection, particularly against severe disease. These data should help guide policy decisions and mitigate vaccine hesitancy among people who had SARS-CoV-2 infection.”

The Comment authors also note that further research is needed regarding the impact of the delta (B.1.617.2) and omicron (B.1.1.529) variants on re-infections.

They add: “Hybrid immunity due to exposure to natural infection and vaccination is likely to be the norm globally and might provide long-term protection even against emerging variants. Besides vaccination, continued surveillance for further emergence of variants for their immune evasiveness and pathogenicity should continue.”

Hybrid immunity bolsters protection observed from infection-driven immunity

The second study, carried out in Sweden, examined both the long-term protection offered by infection-driven immunity from previous SARS-CoV-2 infection, and the potential of additional protection in reinfected people generated by hybrid immunity (a combination of infection-driven immunity and immunity from vaccination).

The researchers used nationwide Swedish registers of SARS-CoV-2 infection with data up to October 2021 [5] to examine three cohorts: unvaccinated individuals with previous SARS-CoV-2 infection (over 2 million individuals), and vaccinated individuals with one (962,000 individuals) or two doses (568,000 individuals) and a previous SARS-CoV-2 infection. The outcomes investigated were risk of reinfection and hospitalisation for 20 months of follow up in those with infection-driven immunity versus those with no immunity, and protection against COVID-19 reinfection and hospitalisation from hybrid immunity versus infection-driven immunity in nine months of follow up.

Infection-driven immunity acquired from previous SARS-CoV-2 infection was found to reduce the risk of reinfection by 95%, and hospitalisation by 87% from 3 months, to up to 20 months after the initial infection. Of the total number of SARS-CoV-2 infection registrations within the study period, 34,090 infections occurred in individuals with infection-driven immunity and 99,168 were in individuals with no immunity (out of a cohort of over 2 million people).

“As expected, there was an increased chance of hospitalisation during the first three months after the initial infection, highlighting the fact that infection-driven immunity is not without risk. However, those who recovered experienced 87% protection against COVID-19 for the rest of the follow up, remaining high for up to 20 months. These findings suggest that any passports used for societal restrictions could consider either a previous infection or vaccination as proof of immunity, as opposed to vaccination only,” says Anna Nordström, co-lead author of the study, Umeå University, Sweden. [1]

Unvaccinated individuals with a documented previous SARS-CoV-2 infection were matched with vaccinated individuals of the same age to assess the effectiveness. Both one- and two-dose hybrid immunity were associated with additional protection against COVID-19 hospitalisation beyond the level of protection afforded by infection-driven immunity alone.

Hybrid immunity provided by one dose of COVID-19 vaccine (alongside infection-driven immunity from previous SARS-CoV-2 infection) lowered the risk of reinfection by 58% two months after vaccination (in 639/481,159 people with hybrid immunity compared to 1,662/481,159 people with infection-driven immunity only). This decreased to 45% in the nine-month follow up. With respect to COVID-19 hospitalisations, eight individuals were hospitalised among individuals with one-dose hybrid immunity compared to 113 individuals with infection-driven immunity.

Hybrid immunity with two doses of vaccine lowered the risk of infection by 66% in the first two months (in 438/283,905 people compared to 808/283,905 people with infection-driven immunity only) and 56% in the nine months follow up. In addition, six individuals were hospitalised among individuals with two-dose hybrid immunity compared to 40 individuals with infection-driven immunity.

The authors acknowledge some limitations with this study including a risk of bias due to the observational nature of this study which may have led to selection bias in individuals without a previous infection and who may be less inclined to take a PCR test compared to individuals with a documented previous infection. Furthermore, this study was not able to evaluate how different variants of COVID-19 affected the results and data on hybrid immunity was based on a small number of cases.

Writing in a linked Comment for the second study, Jennifer Juno of The University of Melbourne, Australia, who wasn’t involved in either study, said: “These data confirm, in a large cohort, the added protective benefit of vaccination among individuals recovered from COVID-19… [and]… clearly demonstrate the benefits of two-dose vaccination for convalescent individuals, both in terms of the durability of immunity and protection from severe disease. Looking forward, the incorporation of infection history in an immune profile of an individual, while justified, brings into question how future booster regimens should be planned for. For instance, are individuals with infection-associated immunity required to obtain two further doses to achieve the level of immunity observed in individuals with no prior infection but receiving 3 doses? Regardless, SARS-CoV-2 infection is clearly a significant contributor to protective immunity, and its interplay with vaccination warrants further longitudinal studies, ultimately providing insights to drive proactive health policies and measures for optimal population-wide immunity in this pandemic.”