Safety and immunogenicity of the iNTS-GMMA vaccine

Thesis

Invasive non-typhoidal Salmonella (iNTS) is a common cause of bacteraemia in sub-Saharan Africa, where it particularly affects children under five. In this thesis, I outline SALVO (Salmonella Vaccine Study in Oxford), a first-in-human phase I randomised placebo-controlled trial investigating the safety and immunogenicity of the iNTS-GMMA vaccine at two dose levels, full dose (40µg O-Antigen) and lower dose (10.6µg O-Antigen) over a three-dose schedule at month 0, 2 and 6. The vaccine is based on outer membrane vesicles (OMVs) from Salmonella Enteritidis (SEn) and Salmonella Typhimurium (STm), which have been genetically modified to increase the production and reduce the toxicity of these OMVs (called Generalised Modules of Membrane Antigens, GMMAs).

The full dose iNTS-GMMA vaccine exhibited an acceptable safety profile up to 28 days after the second vaccination within the limited time points and blinded data assessed. Confirmation of the safety of the vaccine is pending remaining time points and assessment of unblinded data. The full dose iNTS-GMMA vaccine elicited significantly elevated SEn/STm GMMA immunogenicity at day 14-84 following the first vaccination compared with baseline and placebo. All SEn/STm GMMA, IgG and IgA, antibody-dependent monocyte phagocytosis (ADMP), GMMA specific CD3+CD4+ and CD3+CD8+ memory T cells were significantly elevated at day 28 after the first vaccination compared with baseline. Sera obtained following S. Typhi and S. Paratyphi infection contained functional antibodies (ADMP) to SEnGMMA and STmGMMA. Likewise, the iNTS-GMMA vaccine stimulated functional antibodies (ADMP) to S. Paratyphi. O-antigen was the immunodominant antigen within GMMAs to sera following natural infection, iNTS-GMMA vaccination, S. Typhi and S. Paratyphi infection.

Overall, I demonstrate that the full dose iNTS-GMMA vaccine appeared well tolerated (within the limited blinded data assessed) and stimulates a significant multi-faceted immune response up to day 28 following the second vaccination, suggesting the continued advancement of a potential new vaccine against iNTS.

Authors: Hanumunthadu, B

• DOI: 10.5287/ora-zr8wx0zwe
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: invasive non-typhoidal salmonella; iNTS vaccine; iNTS
• Subjects: Salmonella; Clinical trials