Oral immunization with a probiotic cholera vaccine induces broad protective immunity againstVibrio choleraecolonization and disease in mice

Abstract

23Oral cholera vaccines (OCVs) are being increasingly employed, but current killed formulations 24 generally require multiple doses and lack efficacy in young children. We recently developed a 25 new live-attenuated OCV candidate (HaitiV) derived from a Vibrio cholerae strain isolated during 26 the 2010 Haiti cholera epidemic. HaitiV exhibited an unexpected probiotic-like activity in infant 27 rabbits, preventing intestinal colonization and disease by wild-type V. cholerae before the onset 28 of adaptive immunity. However, it remained unknown whether HaitiV would behave similarly to 29 other OCVs to stimulate adaptive immunity against V. cholerae. Here, we orally immunized adult 30 germ-free female mice to test HaitiV's immunogenicity. HaitiV safely and stably colonized 31 vaccinated mice and induced known adaptive immune correlates of cholera protection within 14 32 days of administration. Pups born to immunized mice were protected against lethal challenges of 33 both homologous and heterologous V. cholerae strains. Cross-fostering experiments revealed 34 that protection was not dependent on vaccine colonization in or transmission to the pups. These 35 findings demonstrate the protective immunogenicity of HaitiV and support its development as a 36 new tool for limiting cholera. 37 38

Dissecting serotype-specific contributions to live oral cholera vaccine efficacy

“…An important caveat underlying our findings is that GF mice lack commensal gut microbes and could have altered immune responses to immunization, especially considering recent studies that have highlighted how V. cholerae-microbiota interactions can influence colonization, disease, and development of anti-V. cholerae immunity [48][49][50][51][52] . However, the strong association of VAT induction with protection and superior efficacy of live over inactivated vaccine strains in this model, and our similar findings of OCV function in mice with transiently disrupted microbiomes reinforces the idea that the GF mouse live OCV model holds substantial translational promise 36,37 .…”

“…Pups in all three live vaccine groups were significantly protected from both death and diarrhea caused by challenge with either serotype compared with pups in the FKV group that exhibited similar kinetics of mortality as pups of unvaccinated dams, indicating that the presence of VATs (i.e. seroconversion) is tightly correlated with protection in this model ( Figure 3BC) 36,37 . However, the protective efficacy of the three vaccine serotypes differed depending on the serotype of the challenge strain.…”

“…We used the GF adult mouse oral immunization model to compare the relative potency of the immune responses elicited by these three HaitiV serotype variants in adult female mice 36,39,40 . 3-6-week-old female GF mice (n=5/group) were immunized with a single oral dose of 10 9 CFU of live Ogawa V , Inaba V , Hiko V or formalin-inactivated Hiko V (FKV) ( Figure 1C).…”

“…HaitiV contains a set of genetic modifications that reduce its potential reactogenicity and enhance its biosafety, and allow it to over-produce the non-toxic B subunit of Ctx to boost immunogenicity 35 . In two mouse models, we showed that HaitiV is immunogenic and elicits robust protective adaptive immune responses 36,37 . In addition to its function as a conventional live OCV, HaitiV also has an unprecedented, rapid-acting function that protects animals against lethal V. cholerae challenge within 24 hours post-immunization.…”

Mucosal Vaccination with Lactococcus lactis-Secreting Surface Immunological Protein Induces Humoral and Cellular Immune Protection against Group B Streptococcus in a Murine Model

“…It has been shown that subcutaneous and oral immunization with SIP induces a protective humoral and cellular immune response [ 18 , 19 ]. In the context of oral immunization strategies, the route of administration would be adequate for the generation of mucosal immunity, which has already been proven to generate protection against diseases such as cholera and polio [ 20 , 21 ]. An oral vaccine might be advantageous for the distribution and administration of GBS vaccines, which could improve the uptake of antigen vaccination and overall public health.…”