Study Reveals Impact of Hybrid Immunity and Booster Vaccination on Antibody Waning

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In a recent study published in npj Vaccines, researchers conducted a systematic literature review and meta-analysis to examine the decline in neutralizing antibody (nAb) titers following COVID-19 vaccination.

The study systematically reviewed the evidence of antibody waning within the first six months after receiving the last dose of the primary COVID-19 vaccination compared to booster vaccination.

This analysis included individuals who had not been previously infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as well as those with hybrid immunity. The research encompassed a range of studies, both published and in pre-print form, which explored this phenomenon across different immunological scenarios.

Study: Systematic review and meta-analysis of the factors affecting waning of post-vaccination neutralizing antibody responses against SARS-CoV-2. Image Credit: Billion Photos/


Despite the constant evolution of SARS-CoV-2 and the waning of immunity acquired through vaccines, COVID-19 vaccines continue to confer protection against severe illness and death. However, studies have shown that vaccine effectiveness is lower against Omicron than its predecessors.

Thus, assessing the impact of emerging SARS-CoV-2 variants on the performance of COVID-19 vaccines and the complex biological phenomenon of antibody waning post-vaccination or infection through clinical studies on human subjects is imperative.

Unfortunately, these studies require significant time to receive results. During unavailability or inadequacy of clinical data, laboratory assessments of nAb titers, generated rather quickly, could help inform future vaccination strategies.

However, even these studies are often inadequately powered to provide robust evidence. 

Meta-analysis of data from several studies could help circumvent these limitations and help evaluate the impact of all immunological factors on antibody waning more comprehensively.

About the study

In this study, researchers conducted a thorough search of PubMed, medRxiv, and bioRxiv between December 15, 2021, and January 31, 2023, to identify studies that investigated the impact of booster doses or hybrid immunity on the rate of neutralizing antibody decline.

Out of 347 articles initially identified, only 26 met the criteria for a full-text review. These 26 articles were subject to a systematic review and meta-regression analysis following the PRISMA guidelines.

The meta-analysis was organized into five strata as follows:

1.The first stratum consisted of 18 cohorts of individuals who were infection-naïve, and they had received primary vaccination against the Index strain, defined as either one dose of the Ad26.CoV2.S vaccine or two doses of any other COVID-19 vaccine.

2.The second stratum also included 18 cohorts of infection-naïve individuals, but they had received a booster vaccination against the Index strain, defined as one dose of any COVID-19 vaccine after completing their primary series of vaccinations.

3.The third stratum encompassed 15 cohorts of infection-naïve individuals who had received a booster vaccination specifically targeting the Omicron BA.1 variant.

4.The fourth stratum included eight cohorts of hybrid-immune individuals who had previously been infected with the Index strain and had also received primary vaccination.
5.The fifth stratum involved six cohorts of hybrid-immune individuals who had been previously infected with the Omicron BA.1 variant and had also received primary vaccination.

Notably, all hybrid-immune cohorts included in this meta-analysis were from the pre-Omicron era, which limited analysis of variant-specific assessment of hybrid-immunity. 

The researchers used meta-regressions to evaluate temporal changes in nAb titers against the Wuhan-1, the Index SARS-CoV-2 strain, and Omicron BA.1 for all five strata.

They included studies with six or more cohorts reporting post-vaccination nAb titers for at least two-time points following the last vaccine dose. Another important criterion for inclusion was that these studies used pseudo-or authentic virus neutralization assays.

Further, they deduced average declines in geometric mean titers (GMTs) stratified by vaccine type, the number of vaccine doses, prior infection status, infecting strain, and hybrid immunity.

Furthermore, the researchers systematically assessed the reliability of all 26 included studies and found these fell into one of the four categories based on their reliability scores: high, medium, low, and unclear.

Finally, they used several statistical processes, including estimation of natural logGMT, linear mixed-effects model, and regression analysis, highlighting statistically significant results with p < 0.05.


In this study, the researchers initially screened 8,418 articles, ultimately focusing on 26 studies that primarily reported data on neutralizing antibodies (nAbs) against both the Index strain and Omicron BA.1.

Their analysis, using random effects meta-regression, indicated that the rate of antibody waning was generally similar among cohorts of individuals who were previously infected and those who were infection-naïve, regardless of the number of vaccine doses they received.

The observed reduction in nAb geometric mean titers (GMTs) from months 1 to 6 varied, ranging from a 3.7-fold decrease against the Index strain in hybrid-immune cohorts post-primary vaccination to a 5.9-fold decrease against Omicron BA.1 in infection-naïve cohorts who had received a booster.

Additionally, it was noted that cross-reactive nAbs to Omicron BA.1 decreased faster than Index-specific nAbs in both cohorts, although this difference was not statistically significant (p = 0.67).

Waning rates remained relatively consistent across different vaccine platforms, but the peak GMTs varied widely between studies, resulting in broad confidence intervals (CIs) in the meta-analyses.

Moreover, this study revealed differences in the immunogenicity of various vaccination strategies, with mRNA vaccines producing the highest nAb titers and inactivated vaccines resulting in the lowest.

Individuals who received a less immunogenic primary vaccination regimen saw non-protective nAb titers decline more rapidly, and this effect was more pronounced among those who received only a primary vaccine, compared to hybrid-immune cohorts.

Notably, three infection-naïve cohorts yielded intriguing observations. In one cohort, nAb titers remained consistently low over three months, with no change (short-term). In the other two cohorts, nAb titers against Omicron BA.1 decreased, suggesting breakthrough infections did not occur.

The researchers speculated that the use of a vector vaccine as the last dose in these three cohorts might have elicited more durable nAb responses post-boosting. However, additional studies are needed to explore the potential role of vector vaccines in enhancing long-lasting immune responses.

The study found that a significant majority (88%) of the included studies had medium, low, or unclear reliability scores, primarily due to inadequate reporting quality.

Very few studies had high-reliability scores, indicating challenges in comparing nAb titer data across different studies. Interestingly, differences in nAb peak titers and waning rates between studies with medium to high versus low-reliability scores were not statistically significant.

It's important to note that data on long-term antibody waning, specifically 12 months after the last vaccine dose, were not available. However, since waning rates remained similar post-primary and first booster vaccinations, it's conceivable that they might continue to be similar for subsequent doses.

As the time gap between COVID-19 vaccine doses extends, future research could address the issue of long-term antibody waning, potentially offering insights for more refined vaccination strategies.


This retrospective study strongly reinforces the idea that both SARS-CoV-2 infection and vaccine-induced neutralizing antibodies are critical factors for protection against COVID-19. These factors will remain crucial in shaping future vaccination strategies.

The study's findings emphasize the importance of administering additional booster vaccinations to protect against COVID-19, especially given the emergence of new SARS-CoV-2 variants and the noticeable decline in antibody levels over time.

Furthermore, the research underscores the significance of carefully timing these booster vaccinations based on an individual's history of SARS-CoV-2 infection and prior vaccination.

It's also vital to consider other important factors, such as the overall level of immunity within the population and the risk of severe outcomes, when planning future vaccination strategies.

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