How effective are prior SARS-CoV-2 infections and hybrid immunity against Omicron breakthrough infections?

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

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


The majority of the global population developed hybrid immunity post mass vaccination drives, followed by the advent of the SARS-CoV-2 Omicron (B.1.1.529) variant that caused reinfections due to its immune-evading potential.

About the study

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

The researchers assessed several outcomes related to hybrid immunity, such as hybrid immunity relative to previous 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. Additionally, they used log-odds random-effects meta-regression to estimate the breadth of immune protection against Omicron at one-month intervals throughout the study duration.

The analyses covered studies examining immune protection against Omicron reinfection in which the exposure group comprised individuals with prior infection with any SARS-CoV-2 variant or hybrid immunity. The control group had immune-naive, previously infected, or vaccinated individuals. The researchers determined Omicron infection by whole genomic sequencing or based on dominance periods of the variants per the Global Initiative on Sharing Avian Influenza Data (GISAID) database.

Study findings

Both previous SARS-CoV-2 infection and hybrid immunity conferred adequate protection against Omicron infection(s), but it waned quickly. Moreover, a prior episode of COVID-19 provided higher and more persistent protection against hospitalization or severe COVID-19 than only vaccination. Conversely, individuals with hybrid immunity exhibited more durable protection against all COVID-19 outcomes, emphasizing the significance of vaccinating previously infected individuals.

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

Furthermore, the study results highlighted the need for optimally timing the primary COVID-19 vaccination series and the booster doses for individuals. As is already known, boosting time varies for an individual previously infected with SARS-CoV-2 or who had a breakthrough infection after the beginning of the primary COVID-19 vaccination series compared to an immune-naïve individual. It is reasonable to delay boosting by six months because individuals with a prior infection and fully vaccinated individuals naturally enjoy higher immunity against severe COVID-19.

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

In such countries, they could identify individuals as infected before with an anti-nucleocapsid diagnostic assay to inform recommendations for boosters. This approach, however, does not apply to high-risk groups (e.g., immunocompromised individuals).

The authors cautioned that modifications to COVID-19 vaccination programs might diminish vaccine uptake. So, it is best to keep vaccine rollout simple. Furthermore, the World Health Organization (WHO) has recommended not delaying or excluding individuals from vaccination due to past infections. In addition, boosting might be beneficial before periods of increased COVID-19 incidence, such as in winter, especially when the SARS-CoV-2 variant that caused the past infection is unknown. As is widely known, the prevalence of COVID-19 remains highly underestimated in most countries throughout 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 past SARS-CoV-2 infection rates.

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

Journal 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 previous SARS-CoV-2 infection and hybrid immunity against the omicron variant and severe disease: a systematic review and meta-regression. Lancet Infectious Diseases. doi:

Posted in: Medical Science News | Medical Research News | Disease/Infection News

Tags: Antibodies, Assay, Avian Influenza, Coronavirus, Coronavirus Disease COVID-19, covid-19, Diagnostic, Genomic, Genomic Sequencing, immunity, Infectious Diseases, Influenza, Omicron, Pandemic, Protein, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Syndrome, Vaccine

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Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.

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