Protective Efficacy of Gastrointestinal SARS-CoV-2 Delivery Against Intranasal and Intratracheal SARS-CoV-2 Challenge in Rhesus Macaques

Live oral vaccines have been explored for their protective efficacy against respiratory viruses, particularly for adenovirus serotypes 4 and 7. The potential of a live oral vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), however, remains unclear. In this study, we assessed the immunogenicity of live SARS-CoV-2 delivered to the gastrointestinal tract in rhesus macaques and its protective efficacy against intranasal and intratracheal SARS-CoV-2 challenge. Post-pyloric administration of SARS-CoV-2 by esophagogastroduodenoscopy resulted in limited virus replication in the gastrointestinal tract and minimal to no induction of mucosal antibody titers in rectal swabs, nasal swabs, and bronchoalveolar lavage. Low levels of serum neutralizing antibodies were induced and correlated with modestly diminished viral loads in nasal swabs and bronchoalveolar lavage following intranasal and intratracheal SARS-CoV-2 challenge. Overall, our data show that post-pyloric inoculation of live SARS-CoV-2 is weakly immunogenic and confers partial protection against respiratory SARS-CoV-2 challenge in rhesus macaques. Importance SARS-CoV-2 remains a global threat, despite the rapid deployment but limited coverage of multiple vaccines. Alternative vaccine strategies that have favorable manufacturing timelines, greater ease of distribution and improved coverage may offer significant public health benefits, especially in resource-limited settings. Live oral vaccines have the potential to address some of these limitations; however no studies have yet been conducted to assess the immunogenicity and protective efficacy of a live oral vaccine against SARS-CoV-2. Here we report that oral administration of live SARS-CoV-2 in non-human primates may offer prophylactic benefits, but that formulation and route of administration will require further optimization.

Protective Efficacy of Gastrointestinal SARS-CoV-2 Delivery Against Intranasal and Intratracheal SARS-CoV-2 Challenge in Rhesus Macaques

Live oral vaccines have been explored for their protective efficacy against respiratory viruses, particularly for adenovirus serotypes 4 and 7. The potential of a live oral vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), however, remains unclear. In this study, we assessed the immunogenicity of live SARS-CoV-2 delivered to the gastrointestinal tract in rhesus macaques and its protective efficacy against intranasal and intratracheal SARS-CoV-2 challenge. Post-pyloric administration of SARS-CoV-2 by esophagogastroduodenoscopy resulted in limited virus replication in the gastrointestinal tract and minimal to no induction of mucosal antibody titers in rectal swabs, nasal swabs, and bronchoalveolar lavage. Low levels of serum neutralizing antibodies were induced and correlated with modestly diminished viral loads in nasal swabs and bronchoalveolar lavage following intranasal and intratracheal SARS-CoV-2 challenge. Overall, our data show that post-pyloric inoculation of live SARS-CoV-2 is weakly immunogenic and confers partial protection against respiratory SARS-CoV-2 challenge in rhesus macaques.

Meta-analysis of the effectiveness of pentavalent live oral vaccine for the prevention of severe forms of rotavirus gastroenteritis in children

Rotavirus infection is ubiquitously distributed and represents a global public health problem. Some studies showed that vaccination with pentavalent oral live vaccine was effective in prevention of severe forms of rotavirus gastroenteritis among children up to 3 years of age. Previous randomized placebo-controlled studies assessing this issue were repeatedly conducted. However, due to the features of the epidemiology of pediatric rotavirus infection in Russia, a metaanalysis was conducted in the risk group — children under the age of 3 years by administering a full vaccination course for a single vaccine registered in the Russian Federation. A search was performed by two independent reviewers covering 1994 to February 2019, without restrictions on language, in five databases on medical and biological publications: Russian Science Citation Index, PubMed, Web of Science, MEDLINE, Scopus, and in contents of thematic journals and bibliographic lists. The meta-analysis included multicenter randomized controlled trials comparing the efficacy of placebo and completed full vaccination course with pentavalent live oral rotavirus vaccine in children under 3 years of age. The primary endpoint of the study was the incidence of severe gastroenteritis among children according to the Vesikari evaluation system. Data processing and generation of forest-plots to evaluate summarized results were carried out by the RevMan 5.3 free software distributed on the Cochrane Community website. The implementation of the “trim and fill” method was performed by using Stata 14.2 software. The meta-analysis consisted of 7 original publications performed as multicenter randomized, placebo-controlled double-blind studies. In the experimental and control group there were enrolled 19,384 and 19,425 subjects, respectively. Three-dose vaccination protocol markedly reduced a risk of infection with severe rotavirus gastroenteritis in the experimental group compared to control group, the odds ratio was 0.34 [95%, CI 0.19—0.60]. Cluster analysis also confirmed the protective effect of the full vaccination course. Group assessment of the vaccination effectiveness against rotavirus infection in countries of Africa and Southeast Asia showed significant protection, the odds ratio was 0.60 [95%, CI 0.52—0.70]. While evaluating the effectiveness of vaccination against rotavirus infection in Finland, the odds ratio was set at the level of statistical significance and reached 0.07 [95%, CI 0.04—0.11]. Thus, a full vaccination course with pentavalent live oral vaccine against rotavirus infection lowers a risk of developing severe rotavirus gastroenteritis in young children.

Evaluation of a Salmonella Strain Isolated from Honeybee Gut as a Potential Live Oral Vaccine Against Lethal Infection of Salmonella Typhimurium

In this research, Salmonella species were isolated from the animal, insect and human enteric sources in Faisalabad, Punjab, Pakistan. These species were characterized by different microbiological and molecular techniques including polymerase chain reaction (PCR) by amplification of the 16S rRNA gene. Furthermore, sequencing of the amplicons confirmed all ten isolates as Salmonella strains. The antigenic cross-reactivity was found maximum between the HB1 (strain isolated from honeybee) antiserum and its antigen with an antibody titer of 1:128, while the HB1 antiserum showed a cross-reactive titer range of 1:8 to 1:64. On the basis of the highest geometric mean titer (GMT) shown by the antiserum of the HB1 antigen, it was selected as the best candidate for a cross-reactive live Salmonella oral antigen. Moreover, the HB1 antigen was used a live oral antigen (1 × 1010 CFU/ml) in a safety test in rabbits and proved to be avirulent. During the animal trial, three different oral doses of the HB1 live oral antigen were evaluated in four different rabbits’ groups (R1, R2, R3, and R4). The dose number 2 of 0.5 ml (two drops orally and repeated after one week) gave the best GMT measured by indirect hemagglutination (IHA) as compared to the other two doses, while R4 group was kept as control. Results of the challenge protection test also validated the efficacy of the double dose of the HB1 live vaccine, which gave the highest survival percentage. Results of this study lay the foundation for a potential cross-reactive live oral Salmonella vaccine that has proved to be immunogenic in rabbits.

Vaccine potential of a nonflagellated, virulence-plasmid-cured (fliD–, pSEVΔ) mutant of Salmonella Enteritidis for chickens

The aim of these studies was to assess residual virulence and early protective capacity of a negatively markered live attenuated vaccine candidate Salmonella Enteritidis mutant against a highly virulent S. Enteritidis strain using a dayold chicken model. Nonflagellated FliD negative mutants of Salmonella Enteritidis 11 (SE11) with and without the virulence plasmid proved to be sufficiently attenuated (limited invasiveness in vitro/in vivo) without reduced ability to colonise chicken gut. The early protective activity of a nonflagellated, virulence-plasmidcured (fliD–, pSEVΔ) mutant against organ invasion, caecal colonisation and faecal shedding by the highly virulent challenge strain S. Enteritidis 147 NalR proved to be effective and safe. The innate and adaptive immunity was demonstrable during the first four weeks of life, and the serological response was clearly distinguishable from the response induced by the wild parental strain. In conclusion, we provided data for the first time about a virulence-plasmid-cured, nonflagellated mutant of S. Enteritidis to serve as a basis for development of a negatively markered potential live oral vaccine against virulent S. Enteritidis in chicken.

In VitroProperties of a Listeria monocytogenes Bacteriophage-Resistant Mutant Predict Its Efficacy as a Live Oral Vaccine Strain

ABSTRACTAListeria monocytogenesglcVmutation precludes the binding of certain listerial phages and produces a profound attenuation characterized by the absence of detectable mutants in the livers and spleens of orally inoculated mice.Invitro, we found that the mutant formed plaques on mouse enterocyte monolayers as efficiently as the parent but the plaques formed were smaller. Intracellular growth rate determinations and examination of infected enterocytes by light and fluorescence microscopy established that the mutant was impaired not in intracellular growth rate but in cell-to-cell spreading. Because this property is shared by other immunogenic mutants (e.g.,actAmutants), ourglcVmutant was tested for vaccine efficacy. Oral immunization with the mutant and subsequent oral challenge (22 days postvaccination) with the parent revealed a ca. 10,000-fold increase in protection afforded by the mutant compared to sham-vaccinated controls. TheglcVmutant did not stimulate innate immunity under the dose and route employed for vaccination, and an infectivity index time course experiment revealed pronounced mutant persistence in Peyer's patches. The immunogenicity of theglcVmutant compared to an isogenicactAmutant reference strain was next tested in an experiment with a challenge given 52 days postvaccination. Both mutant strains showed scant vital organ infectivity and high levels of protection similar to those seen using theglcVmutant in the 22-day postvaccination challenge. Our results indicate that oral administration of a profoundly attenuated listerial mutant can safely elicit solid protective immunity.