Oral Presentation 14th Lorne Infection and Immunity 2024

Specific and off-target immune responses following COVID-19 vaccination with ChAdOx1-S and BNT162b2 COVID-19 vaccines (#26)

Nicole L Messina 1 2 , Susie Germano 1 , Rebecca McElroy 1 , Rhian Bonnici 1 , Branka Grubor-Bauk 3 , David J Lynn 4 5 , Ellie McDonald 1 , Suellen Nicholson 6 , Kirsten P Perrett 2 7 8 , Laure F Pittet 1 2 9 , Rajeev Rudraraju 10 , Natalie E Stevens 4 5 , Kanta Subbarao 10 11 , Nigel Curtis 1 2 12 13
  1. Infection, Immunity and Global Health theme, Murdoch Children’s Research Institute, Parkville, Victoria, Australia
  2. Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia
  3. Viral Immunology Group, University of Adelaide and Basil Hetzel Institute for Translational Health Research, Adelaide, Australia
  4. Precision Medicine Theme Australia, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
  5. Flinders Health and Medical Research Institute, Flinders University, Adelaide, South Australia, Australia
  6. Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital, The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
  7. Population Allergy, Murdoch Children's Research Institute, Parkville, Victoria, Australia
  8. Department of Allergy and Immunology, The Royal Children's Hospital Melbourne, Parkville, Victoria, Australia
  9. Paediatric Infectious Diseases Unit, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
  10. Department of Microbiology and Immunology, University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
  11. WHO Collaborating Centre for Reference and Research on Influenza, Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
  12. Infectious Diseases Unit, The Royal Children’s Hospital Melbourne, Parkville, Victoria, Australia
  13. on behalf of the BRACE trial,

The primary goal of vaccination is to induce antigen-specific or cross-protective immune responses against a target pathogen. However, several vaccines, particularly live-attenuated vaccines such as Bacillus Calmette-Guerin (BCG), have beneficial off-target effects. With widespread administrations of COVID-19 vaccines, potential off-target immunological effects have important implications for global health. In this sub-study of participants enrolled in an international randomised controlled trial (BRACE trial, NCT04327206)1, we sought to determine if the adenovirus vector ChAdOx1-S (Oxford-Astra Zeneca) vaccine and modified mRNA BNT162b2 (Pfizer-BioNTech) vaccine have off-target effects on immune responses to unrelated (heterologous) pathogens.

 

Blood samples were collected from 264 healthcare workers before and 28 days after vaccination with ChAdOx1-S or BNT162b2 vaccine. SARS-CoV-2-specific antibodies were measured by ELISA2,3 and whole blood cytokine responses following in vitro stimulation with specific (irradiated SARS-CoV-2)4 or heterologous stimuli (e.g. heat-killed (HK) pathogens or TLR agonists) were measured by multiplex bead array. 

 

ChAdOx1-S vaccination was associated with increased cytokine responses to HK C. albicans and HK S. aureus and decreased cytokine responses to HK E. coli and BCG. Cytokines with altered responses included those involved in T cell responses, lymphocyte homeostasis, pro-inflammatory responses, growth factors and chemokines. BNT162b2 vaccination was associated decreased cytokine responses to HK E. coli and had variable effects on cytokine responses to BCG and R848. Despite decreased responses to BCG and HK E. coli following both vaccines, clusters of cytokines positively correlated with the strongly increased SARS-CoV-2-specific cytokine responses. Direct comparison of the two vaccines also revealed differences in specific and off-target effects of ChAdOx1-S and BNT162b2, manifest as differential cytokine responses, particularly to BCG, HK E. coli, and R848 stimulation.

 

Overall, ChAdOx1-S and BNT162b2 vaccines alter in vitro cytokine responses to unrelated pathogens, indicative of off-target immunological effects. In contrast to the generalized boosting of immune responses to unrelated pathogens proposed for BCG vaccination, off-target effects of ChAdOx1-S and BNT162b2 vaccination are pathogen-dependent and are likely mediated by different mechanisms. These findings have implications for vaccine selection and future vaccine development strategies.

  1. Pittet LF*, Messina NL*, et al. Randomized Trial of BCG Vaccine to Protect against Covid-19 in Health Care Workers. N Engl J Med. 2023 Apr 27;388(17):1582-1596. doi: 10.1056/NEJMoa2212616. *joint first author
  2. Garcia-Valtanen P, et al. SARS-CoV-2 Omicron variant escapes neutralizing antibodies and T cell responses more efficiently than other variants in mild COVID-19 convalescents. Cell Rep Med 2022;3(6):100651.
  3. Bond KA, et al. Longitudinal evaluation of laboratory-based serological assays for SARS-CoV-2 antibody detection. Pathology 2021;53(6):773-779.
  4. Messina NL, et al. Off-target effects of bacillus Calmette-Guérin vaccination on immune responses to SARS-CoV-2: implications for protection against severe COVID-19. Clin Transl Immunology. 2022 Apr 22;11(4):e1387. doi: 10.1002/cti2.1387.