Development of Human Vectored Brucellosis Vaccine Formulation: Assessment of Safety and Protectiveness of Influenza Viral Vectors Expressing Brucella Immunodominant Proteins in Mice and Guinea Pigs

Abstract

In this paper, we first used recombinant influenza viral vector (rIVV) subtype H5N1 expressing from the open reading frame of NS1 80 and NS1 124 amino acids of Brucella outer membrane proteins (Omp) 16 and 19, ribosomal L7/L12, and Cu-Zn superoxide dismutase (SOD) proteins to develop a human brucellosis vaccine. We made 18 combinations of IVVs in mono-, bi-, and tetravalent vaccine formulations and tested them on mice to select the safest and most effective vaccine samples. Then, the most effective vaccine candidates were further tested on guinea pigs. Safety of the rIVV-based vaccine candidate was evaluated by a mouse weight-gain test. Mice and guinea pigs were challenged with the virulent strain B. melitensis 16M. The protective effect of the rIVV-based vaccine candidate was assessed by quantitation of Brucella colonization in tissues and organs of challenged animals. All vaccine formulations were safe in mice. Tested vaccine formulations, as well as the commercial B. melitensis Rev.1 vaccine, have been found to protect mice from B. melitensis 16M infection within the range of 1.6 to 2.97 log10 units ( P < 0.05 ). Tetravalent vaccine formulations from the position of NS1 80 amino acids ( 0.2 ± 0.4 ), as well as the commercial B. melitensis Rev.1 vaccine ( 1.2 ± 2.6 ), have been found to protect guinea pigs from B. melitensis 16M infection at a significant level ( P < 0.05 ). Thus, tetravalent vaccine formulation Flu-NS1-80-Omp16+Flu-NS1-80-L7/L12+Flu-NS1-80-Omp19+Flu-NS1-80-SOD was chosen as a potential vaccine candidate for further development of an effective human vaccine against brucellosis. These results show a promising future for the development of a safe human vaccine against brucellosis based on rIVVs.

Prophylactic vaccine delivery systems against epidemic infectious diseases

“…After immunization with recombinant influenza A viruses of the subtypes H5N1 and H1N1 expressing Brucella protective antigen (ribosomal protein L7/L12 or Omp16), a strong cellular immune response and protective effect were induced, even comparable with those induced by a commercial B. abortus S19 vaccine [180] . Further, a tetravalent vaccine formulation (expressing Omp16, L7/L12, Omp19, and Cu-Zn SOD in recombinant influenza viral vector subtype H5N1 without an adjuvant) was developed to prevent human brucellosis [181] , [240] . In addition, because Brucella can infect people of any age, the long-term protection of this viral vector vaccine also needs to be considered.…”

Registered Influenza Viral Vector Based Brucella abortus Vaccine for Cattle in Kazakhstan: Age-Wise Safety and Efficacy Studies

“…In addition, it does not present any serious risk to human health ( Ferko et al., 2004 ) unlike other commercial Brucella vaccines ( Spink et al., 1962 ; Beckett and MacDiarmid, 1985 ; Schurig et al., 1991 ). This is evidenced by the fact that research is currently under way using IVV platform to develop a brucellosis vaccine for humans ( Bugybayeva et al., 2020 ; Bugybayeva et al., 2021 ). Another important advantage of Flu-BA vaccine is that it is in line with the DIVA strategy, which allowed B. abortus RB-51 to virtually replace the earlier B. abortus S19 vaccine from the market.…”

Evaluation of Brucellosis Vaccines: A Comprehensive Review

“…The main concern is related to the interspecies transmission of the disease from birds to humans, which could lead to human disease. Although the replication capacity of this virus has been limited in this vaccine by eliminating the proteolytic cleavage site in HA, the risk of pandemic strains must be considered ( 52 ). Lactic acid bacteria (LAB) are also considered a desirable antigen delivery system for mucosal immunization.…”

“…The results of this study indicated that this formulation had a high level of safety and efficacy. This research is an important report on the development of a safe and protective vaccine against human brucellosis ( 52 ). In another study, recombinant influenza A viruses of the subtypes H5N1 and H1N1, expressing L7/L12 or Omp16, were developed and shown to elicit Th1 CD4 + and CD8 + T-cell immune responses and confer good protection against challenge ( 61 ).…”

“…The majority of these vaccines designed with regard to new technologies showed the enhanced immune responses and protective immunity against brucellosis in mice, livestock, and guinea pig models. For example, Bugybayeva et al ( 52 ) indicated that the tetravalent vaccine formulation Flu-NS1-80-Omp16+Flu-NS1-80-L7/L12+Flu-NS1-80-Omp19+Flu-NS1-80-SOD protected guinea pigs from B. melitensis 16M infection at a significant level ( P < 0.05). Thus, this vaccine can be chosen as a potential vaccine candidate for further development of an effective human vaccine against brucellosis.…”