In a recent study published on medRxiv* preprint server, researchers in the UK studied the effect of two doses of Pfizer/BioNTech BNT162b2 vaccine or vaccination against Oxford/AstraZeneca AZ1222 2019 coronavirus disease (COVID-19) and a subsequent BNT162b2 booster dose in a cohort of healthcare workers (HCWs) over six to nine months.
Study: Evolution of long-term hybrid immunity in healthcare workers after different COVID-19 vaccination regimens: a longitudinal observational cohort study. Image Credit: M-Foto/Shutterstock
In their previous study of protective T-cell immunity in healthcare workers called PITCH, the authors observed that prior infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impacted cellular and humoral immunity induced after BNT162b2 vaccination, with particular emphasis on long (six to seven weeks) and short (three to four) dosing intervals.
Studies have not examined the long-term impacts of prior exposure, vaccine regimen, and type on T cell responses. In the absence of persistent immune protection conferred by T cells, COVID-19 could progress to a serious form resulting in the death of the patient.
Therefore, it is essential to characterize the generation and maintenance of antibody and T cell responses against SARS-CoV-2 after infection and vaccination, alone or in combination. Additionally, this information could help determine future vaccination policies for those most at risk to prioritize them for additional booster shots and monoclonal antibody treatments.
About the study
In the current study, researchers characterized the long-term adaptive and humoral immune responses in healthcare workers who had received three doses of a COVID-19 vaccine, with particular emphasis on the impact of treatment regimen, vaccine type and previous infection.
They reported robust immunity to the SARS-CoV-2(S) spike, including the Omicron BA.1 variant for three vaccine regimens. The team analyzed the response to BNT162b2 vaccination with short and long interval dosing and two doses of the AZ1222 vaccine after a boost with BNT162b2.
The team sampled eligible healthcare workers between January 4, 2021 and February 15, 2022, before the emergence of the Omicron BA.1 subvariant in the United Kingdom (UK). They recorded clinical characteristics, including dates of BNT162b2 and AZD1222 vaccination, date of prior SARS-CoV-2 infection, time from symptom onset to sampling, age, gender and ethnicity of eligible participants.
Additionally, the team randomly selected 95 healthcare workers from the three vaccine regimens who had previously been infected with SARS-CoV-2. They obtained their serum samples and used intracellular cytokine staining (ICS) to characterize their T-cell responses. From this subset, they selected 73 people, with 27 participants from the BNT162b2 long and short interval groups. and 19 participants from the AZD1222 group. Finally, they subjected their samples to a T-cell proliferation assay to assess the magnitude of memory responses to SARS-CoV-2 S, membrane (M), and nucleocapsid protein (N) in the group of differentiation (CD)4+ and CD8+ Pool of T lymphocytes.
Study design Schematic representation of time points for vaccination and phlebotomy. Figure created using Biorender.
The findings were consistent with a previous, more in-depth SARS-CoV-2 Immunity and Reinfection Evaluation (SIREN) study. Furthermore, the authors observed no decrease in T-cell responses over time, regardless of the vaccination regimen. However, the booster shot diminished the impact of prior infection on binding antibody responses.
The dynamics of BNT162b2 boost-induced immune responses varied across SARS-CoV-2 variants. While binding and neutralizing antibodies declined within six months of the second dose, B and T cell ELISpot responses declined significantly less over the same period. After six months from the second vaccine dose, the T cells proliferated and secreted multiple cytokines, indicating that they retained a wide range of memory functions.
Nevertheless, the boost enhanced all immune responses, although the increase in T cell response was much smaller. Additionally, the booster shot significantly enhanced the ability to neutralize the antibody response. The results confirmed that while a booster injection does not alter overall levels of binding antibodies, it significantly improves the quality of antibody responses.
In previously infected individuals, a booster shot induced a detectable T-cell response and helped preserve vaccine efficacy against hospitalization. Compared to antibodies, T cells have a wider range of available epitopes, so their responses are much less affected by emerging SARS-CoV-2 variants.
Neutralizing antibody titer profiles against SARS-CoV-2 variants of concern 6 months after 2 doses of BNT162b2 or AZ1222 and 1 month after a third vaccine with BNT162b2. Neutralizing antibodies against isolate Victoria (orange), delta (B.1.617.2, purple) and omicron BA.1 (B.1.1.529 BA.1, blue) collected from infection naïve participants after receiving 2 doses of BNT162b2 (Pfizer-BioNTech) vaccine delivered in a short (“Short”, 3-5 weeks, n=20) or long (“Long”, 6-17 weeks, n=20) dosing interval, or 2 doses of AZD1222 (AstraZeneca) vaccine (“AZ”, n=16) are shown in (4A) 6 months after the second dose, and (4B) for the same individuals, 1 month after a third “booster” dose with BNT162b2 for all participants. Geometric mean neutralizing titers with 95% confidence intervals are shown. Focus Reduction Neutralization Assay 50 (FRNT50) is the reciprocal dilution of serum concentration necessary to produce a 50% reduction in focus-forming viral units in Vero cells (ATCC CCL-81). (4C) Comparison of data from (4A) and (4B), plotted as means with error bars by vaccination regimen. V2+6 months = 6 months after the second vaccine, V3+1 month = 1 month after the third BNT162b2 “booster” vaccine. The range of fold change (median) between V2+6 months and V3+1 months for the three vaccination schedules (short – dotted line, long – solid line and AZ – dotted line) is indicated in parentheses for each variant. The data in (4A), (4B) and (4C) of the Short group (n = 20) have already been published (Dejnirattisai, Huo et al. 2022). (4D) Impact of short or long dosing interval of BNT162b2 vaccine and AZ on the ability of sera to inhibit ACE2 binding to peak SARS-CoV-2 (Victoria isolate, delta (B .1.617.2), Omicron BA.1 (B. 1.1.529 BA.1), alpha (B.1.1.7), beta (B.1.351) and gamma (P.1) 6 months after the second dose and (4E) 1 month after a third “booster” dose with BNT162b2. ACE2 inhibition was analyzed using a multiplexed MSD® assay. Data are displayed as percent inhibition. Bars represent the median with 95% confidence intervals Naive, short: n = 20; Naive, long: n = 20; Naive, AZ: n=16 for V2 + 6 months; Naive, Short: n=19; Naive, Long: n=20; Naive, AZ: n=10 for V3 + 1 month Vaccination regimens were compared to Kruskal-Wallis non-parametric test and Dunn’s multiple comparison tests, with two-sided p values shown above bond lines when two-sided p
Regardless of vaccine type and treatment regimens, vaccination against COVID-19 induced a stable pool of memory T cells that protected against severe disease in people with or without prior infection. In addition, a booster injection conferred additional protection beyond the primary vaccination. It helped mount a more robust immune response to the Omicron BA.1 variant by inducing better antibody recognition and potentially reducing hospitalization rates in people with preexisting comorbidities. As a result, several countries, such as the United Kingdom, vaccinate their immunocompromised populations with a fourth or even a fifth dose of vaccine.
Overall, the study provides much-needed insight into the evolution of hybrid immunity driven by exposure to novel SARS-CoV-2 variants in vaccinated populations. Further studies should continue to investigate the role of booster vaccinations in more vulnerable populations (eg, healthcare workers) in mitigating nosocomial transmission of SARS-CoV-2 and the risks of Long COVID.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be considered conclusive, guide clinical practice/health-related behaviors, or treated as established information.
- Evolution of long-term hybrid immunity in healthcare workers after different COVID-19 vaccination regimens: a longitudinal observational cohort study, Shona C Moore, Barbara Kronsteiner, Stephanie Longet, Sandra Adele, Alexandra S Deeks, Chang Liu, Wanwisa Dejnirattisai, Laura Silva Reyes, Naomi Meardon, Sian Faustini, Saly Al-Taei, Tom Tipton, Luisa M Hering, Adrienn Angyal, Rebecca Brown, Alexander R Nicols, Susan L Dobson, Piyada Supasa, Aekkachai Tuekprakhon, Andrew Cross, Jessica K Tyerman, Hailey Hornsby, Irina Grouneva, Megan Plowright, Peijun Zhang, Thomas AH Newman, Jeremy M. Nell, Priyanka Abraham, Mohammad Ali, Tom Malone, Isabel Neale, Eloise Phillips, Joseph D. Wilson, Adrian Shields, Emily C. Horner, Lucy H. Booth, Lizzie Stafford, Sagida Bibi, Daniel G. Wootton, Alexander J. Mentzer, Christopher P. Conlon, Katie Jeffery , Philippa C. Matthews, Andrew J. Pollard, Anthony Brown, Sarah L. Rowland-Jones, Juthathip Mongkolsapaya, Rebecca P. Payne, Christina Dold, Teresa Lambe, James ED Thaventhiran, Gavin Screaton, Eleanor Barnes, Susan Hopkins, Victoria Hall , Christopher JA Duncan, Alex Richter Richter, Miles Carroll, j EU Shan I. de Silva, Paul Klenerman, Susanna Dunachie, Lance Turtle, preprint medRxiv 2022, DOI: https://doi.org/10.1101/2022.06.06.22275865, https://www.medrxiv.org/content/10.1101/2022.06.06.22275865v1