Leveraging Beneficial Off-Target Effects of Live-Attenuated Rotavirus Vaccines

Prisca Benedicto-Matambo^{1

2

3}, Julie E Bines⁴, Chikondi Malamba-Banda^{1

2

3

5}, Isaac T Shawa^{1

3}, Kayla Barnes^{1

6}, Arox W Kamng'ona^{1

7}, Daniel Hungerford^{2

8}, Kondwani C Jambo^{1

9}, Miren Iturriza-Gomara^{2

8

10}, Nigel A Cunliffe^{2

8}, Katie L Flanagan^{11

12

13}, Khuzwayo C Jere^{1

2

3

8}

Affiliations

¹ Virology Research Group, Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre 312225, Malawi.
² Centre for Global Vaccine Research, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool L69 7BE, UK.
³ Department of Medical Laboratory Sciences, Faculty of Biomedical Sciences and Health Professions, College of Medicine, Kamuzu University of Health Sciences, Blantyre 312225, Malawi.
⁴ Enteric Diseases Group, Murdoch Children's Research Institute, Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital and Department of Paediatrics, The University of Melbourne, Parkville, VIC 3052, Australia.
⁵ Department of Biological Sciences, Academy of Medical Sciences, Malawi University of Science and Technology, Blantyre 312225, Malawi.
⁶ Harvard School of Public Health, Boston, MA 02115, USA.
⁷ Department of Biomedical Sciences, Faculty of Biomedical Sciences and Health Profession, College of Medicine, Kamuzu University of Health Sciences, Blantyre 312225, Malawi.
⁸ NIHR Health Protection Research Unit in Gastrointestinal Infections, University of Liverpool, Liverpool L69 7BE, UK.
⁹ Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK.
¹⁰ Centre for Vaccine Innovation and Access, Program for Appropriate Technology in Health (PATH), 1218 Geneva, Switzerland.
¹¹ School of Medicine, University of Tasmania, Hobart, TAS 7005, Australia.
¹² School of Health and Biomedical Science, Royal Melbourne Institute of Technology (RMIT), Bundoora, VIC 3083, Australia.
¹³ Department of Immunology and Pathology, Monash University, Melbourne, VIC 3004, Australia.

PMID: 35335050
PMCID: PMC8948921
DOI: 10.3390/vaccines10030418

Review

Leveraging Beneficial Off-Target Effects of Live-Attenuated Rotavirus Vaccines

Prisca Benedicto-Matambo et al. Vaccines (Basel). 2022.

. 2022 Mar 10;10(3):418.

doi: 10.3390/vaccines10030418.

Authors

Affiliations

¹ Virology Research Group, Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre 312225, Malawi.
² Centre for Global Vaccine Research, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool L69 7BE, UK.
³ Department of Medical Laboratory Sciences, Faculty of Biomedical Sciences and Health Professions, College of Medicine, Kamuzu University of Health Sciences, Blantyre 312225, Malawi.
⁴ Enteric Diseases Group, Murdoch Children's Research Institute, Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital and Department of Paediatrics, The University of Melbourne, Parkville, VIC 3052, Australia.
⁵ Department of Biological Sciences, Academy of Medical Sciences, Malawi University of Science and Technology, Blantyre 312225, Malawi.
⁶ Harvard School of Public Health, Boston, MA 02115, USA.
⁷ Department of Biomedical Sciences, Faculty of Biomedical Sciences and Health Profession, College of Medicine, Kamuzu University of Health Sciences, Blantyre 312225, Malawi.
⁸ NIHR Health Protection Research Unit in Gastrointestinal Infections, University of Liverpool, Liverpool L69 7BE, UK.
⁹ Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK.
¹⁰ Centre for Vaccine Innovation and Access, Program for Appropriate Technology in Health (PATH), 1218 Geneva, Switzerland.
¹¹ School of Medicine, University of Tasmania, Hobart, TAS 7005, Australia.
¹² School of Health and Biomedical Science, Royal Melbourne Institute of Technology (RMIT), Bundoora, VIC 3083, Australia.
¹³ Department of Immunology and Pathology, Monash University, Melbourne, VIC 3004, Australia.

PMID: 35335050
PMCID: PMC8948921
DOI: 10.3390/vaccines10030418

Abstract

Following the introduction of live-attenuated rotavirus vaccines in many countries, a notable reduction in deaths and hospitalisations associated with diarrhoea in children <5 years of age has been reported. There is growing evidence to suggest that live-attenuated vaccines also provide protection against other infections beyond the vaccine-targeted pathogens. These so called off-target effects of vaccination have been associated with the tuberculosis vaccine Bacille Calmette Guérin (BCG), measles, oral polio and recently salmonella vaccines, and are thought to be mediated by modified innate and possibly adaptive immunity. Indeed, rotavirus vaccines have been reported to provide greater than expected reductions in acute gastroenteritis caused by other enteropathogens, that have mostly been attributed to herd protection and prior underestimation of rotavirus disease. Whether rotavirus vaccines also alter the immune system to reduce non targeted gastrointestinal infections has not been studied directly. Here we review the current understanding of the mechanisms underlying off-target effects of vaccines and propose a mechanism by which the live-attenuated neonatal rotavirus vaccine, RV3-BB, could promote protection beyond the targeted pathogen. Finally, we consider how vaccine developers may leverage these properties to improve health outcomes in children, particularly those in low-income countries where disease burden and mortality is disproportionately high relative to developed countries.

Keywords: RV3-BB; epigenetic modulation; live attenuated; neonatal; off-target effects; rotavirus.

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Conflict of interest statement

N.A.C. received research grant support outside of the submitted work and honoraria for participation in Data Safety Monitoring Boards from GlaxoSmithKline Biologicals. D.H. received research grant support outside of the submitted work from GlaxoSmithKline Biologicals and Sanofi Pasteur and Merck and Co. after the closure of Sanofi Pasteur-MSD in December 2016. M.I.-G. received research grant support, outside of the submitted work, from GlaxoSmithKline Biologicals, Sanofi Pasteur and Merck and Co. (Kenilworth, NJ, USA) after the closure of Sanofi Pasteur-MSD in December 2016. M.I.G also reports personal fees for consultancy, outside the submitted work, from GlaxoSmithKline Biologicals. J.E.B. is the Director of the Australian Rotavirus Surveillance Program funded by the Australian Government Department of Health and GlaxoSmithKline. Murdoch Children’s Research Institute holds the patent for the RV3-BB vaccine. K.L.F. is a member of the Australian Technical Advisory Group on Immunisation noting that this paper represents her own personal view; received honoraria as a member of the vaccine advisory boards for Seqiris and Sanofi Pasteur in the last 5 years.

Figures

**Figure 1**
Rotavirus vaccine candidates in development as of March 2021 [5,6]. Abbreviations: BRV = bovine rotavirus pentavalent vaccine, VLP = virus-like particle, RV = Rotavirus vaccine, CDC = Centre for Disease Control.

**Figure 2**
Illustration of potential beneficial off-target effects of live-attenuated RV3-BB vaccine: At birth and in younger infants, the immune system generally favours inhibition of Th1 and innate responses (A). Live-attenuated vaccines such as RV3-BB administered at birth (B) would circumvent the imbalance towards enhanced immune responses (C) [30,100,102].

**Figure 3**
Potential areas that require further study in the context of off-target effects of vaccination. Factors with potential to influence induction of off-target effects include geographical setting, sex/genetics, vaccine type, performance and vaccine co-administration, vaccine timing, composition of gut microbiome, prior maternal exposure to vaccine or microbes and disease burden in endemic settings. We hypothesise that a live-attenuated rotavirus vaccine (RV3-BB) may cause the development of beneficial off-target vaccine effects when administered at birth, with the potential to interact with sex and infant gut microbiome contributing to overall reduced infant mortality.

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References

1. WHO Children: Improving Survival and Well-Being. [(accessed on 11 October 2021)]. Available online: https://www.who.int/news-room/fact-sheets/detail/children-reducing-morta....
1. Clark A., Black R., Tate J., Roose A., Kotloff K., Lam D., Blackwelder W., Parashar U., Lanata C., Kang G., et al. Estimating global, regional and national rotavirus deaths in children aged <5 years. PLoS ONE. 2017;12:e0183392. - PMC - PubMed
1. WHO Diarrhoeal Disease. [(accessed on 11 October 2021)]. Available online: https://www.who.int/news-room/fact-sheets/detail/diarrhoeal-disease.
1. WHO Vaccines and Immunization 2021. [(accessed on 8 December 2021)]. Available online: https://www.who.int/health-topics/vaccines-and-immunization#tab=tab_1.
1. Cárcamo-Calvo R., Muñoz C., Buesa J., Rodríguez-Díaz J., Gozalbo-Rovira R. The rotavirus vaccine landscape, an update. Pathogens. 2021;10:520. doi: 10.3390/pathogens10050520. - DOI - PMC - PubMed

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Leveraging Beneficial Off-Target Effects of Live-Attenuated Rotavirus Vaccines

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Leveraging Beneficial Off-Target Effects of Live-Attenuated Rotavirus Vaccines

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