Study: Protective effectiveness of previous SARS-CoV-2 infection and hybrid immunity against the omicron variant and severe disease: a systematic review and meta-regression. Image Credit: CI Photos/Shutterstock

How effective are previous SARS-CoV-2 infections and hybrid immunity against emerging infections from Omicron?

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In a recent article published in Lancet Infectious Diseases, investigators conducted a systematic review and meta-regression study to determine the breadth and duration of protective immunity conferred by previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and hybrid immunity. They evaluated this data evidence against infection caused by SARS-CoV-2 Omicron.

Study: Protective effectiveness of prior SARS-CoV-2 infection and hybrid immunity against the omicron variant and severe disease: a systematic review and meta-regression. Image Credit: CI Photos/Shutterstock


Mass vaccination campaigns followed hybrid immunity for the majority of the world population, followed by the advent of the SARS-CoV-2 Omicron variant (B.1.1.529) that caused reinfections due to its potential for immune evasion.

About the study

For the present study, the investigators searched several databases, including MEDLINE, European PubMed Central, and, to name a few, during the period from January 1, 2020 to June 1, 2022. They searched cohorts, case-control, and cross-sectional studies using keywords related to SARS-CoV-2, its prior infection, reinfection, presence of antibodies, and hybrid immunity.

The investigators evaluated several outcomes related to hybrid immunity, such as hybrid immunity relative to prior infection alone, vaccination alone, and hybrid immunity with fewer vaccine doses. They also determined the risk of bias in the studies covered in the study analysis. In addition, they used log-odds random-effects meta-regression to estimate the amplitude of immune protection against Omicron at one-month intervals throughout the duration of the study.

Analyzes covered studies examining immune protection against Omicron reinfection where the exposure group included people with prior infection with any SARS-CoV-2 variant or hybrid immunity. The control group had immunonaive, previously infected or vaccinated individuals. Investigators determined Omicron infection using whole genomic sequencing or based on variant dominance periods based on the Global Initiative for Avian Influenza Data Sharing (GISAID) database.

Study findings

Both prior SARS-CoV-2 infection and hybrid immunity provided adequate protection against Omicron infections, but it declined rapidly. Furthermore, a prior episode of COVID-19 provided greater and more persistent protection against hospitalization or severe COVID-19 than vaccination alone. In contrast, people with hybrid immunity exhibited longer lasting protection against all COVID-19 outcomes, emphasizing the importance of vaccinating previously infected people.

Since infection-induced protection against progressive infection decreases rapidly and vaccination increases the durability of this protection; therefore, vaccination is a reliable intervention to thwart the severe outcomes of COVID-19 and reduce post-COVID-19 complications, including cardiovascular and neurological sequelae.

In addition, the study results highlighted the need to optimally schedule the primary COVID-19 vaccination series and booster doses for individuals. As is known, the booster timing varies for a person previously infected with SARS-CoV-2 or who had advanced infection after the start of the primary COVID-19 vaccination series compared to a person with no prior immunity. It is reasonable to delay the booster by six months because people with a prior infection and fully vaccinated people naturally enjoy increased immunity against severe COVID-19.

More importantly, the researchers advocated conducting serological surveys to estimate prior infection-induced seroprevalence at the population level. This is so because the ideal number of vaccine doses and the interval between doses differ mostly for different population-level settings. This should be the basis of national vaccination policies in many countries, especially those that do not use inactivated vaccines against COVID-19. Another example could be countries that only used vaccines based on the SARS-CoV-2 spike (S) protein.

In such countries, they could identify people as infected earlier with an anti-nucleocapsid diagnostic assay to inform recommendations for boosters. This approach, however, is not applicable to high-risk groups (eg, immunocompromised people).

The authors cautioned that changes to vaccination schedules against COVID-19 could decrease uptake of the vaccine. Therefore, it is best to keep vaccine implementation simple. Additionally, the World Health Organization (WHO) has recommended not to delay or exclude people from vaccination because of past infections. Furthermore, the booster could be beneficial before periods of highest incidence of COVID-19, such as in winter, especially when the variant of SARS-CoV-2 that caused the past infection is unknown. As is well known, the prevalence of COVID-19 remains grossly underestimated in most countries during the pandemic.


The study findings clarified the substantial durability of hybrid immunity that could help inform the timing of vaccination programs in populations with higher rates of SARS-CoV-2 infection in the past.

Future studies should evaluate the protective effect of hybrid immunity against hospitalization or severe illness because these two outcomes drive most COVID-19 policy decisions. Therefore, it is crucial to know how much immunity induced by hybrid immunity wanes over a prolonged period, particularly amid the arrival of worrying new variants of SARS-CoV-2. Such precise quantification of the durability of this protection could help inform the need for and timing of booster vaccinations.

Magazine reference:

  • Niklas Bobrovitz, Harriet Ware, Xiaomeng Ma, Zihan Li, Reza Hosseini, Christian Cao, Anabel Selemon, Mairead Whelan, Zahra Premji, Hanane Issa, Brianna Cheng, Laith J Abu Raddad, David L Buckeridge, Maria D Van Kerkhove, Vanessa Piechotta, Melissa M Higdon, Annelies Wilder-Smith, Isabel Bergeri, Daniel R Feikin, Rahul K Arora, Minal K Patel, Lorenzo Subissi. (2023). Protective effectiveness of prior SARS-CoV-2 infection and hybrid immunity against the omicron variant and severe disease: a systematic review and meta-regression. Lancet Infectious Diseases. doi:

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