Rift Valley fever MP-12 vaccine Phase 2 clinical trial: Safety, immunogenicity, and genetic characterization of virus isolates

Abstract

An outbreak or deliberate release of Rift Valley fever (RVF) virus could have serious public health and socioeconomic consequences. A safe RVF vaccine capable of eliciting long-lasting immunity after a single injection is urgently needed. The live attenuated RVF MP-12 vaccine candidate has shown promise in Phase 1 clinical trials; no evidence of reversion to virulence has been identified in numerous animal studies. The objective of this Phase 2 clinical trial was to (a) further examine the safety and immunogenicity of RVF MP-12 in RVF virus–naïve humans and (b) characterize isolates of RVF MP-12 virus recovered from the blood of vaccinated subjects to evaluate the genetic stability of MP-12 attenuation. We found that RVF MP-12 was well tolerated, causing mostly mild reactions that resolved without sequelae. Of 19 subjects, 18 (95%) and 19 (100%) achieved, respectively, 80% and 50% plaque reduction neutralization titers (PRNT80 and PRNT50) ≥ 1:20 by postvaccination day 28. All 18 PRNT80 responders maintained PRNT80 and PRNT50 ≥ 1:40 until at least postvaccination month 12. Viremia was undetectable in the plasma of any subject by direct plaque assay techniques. However, 5 of 19 vaccinees were positive for MP-12 isolates in plasma by blind passage of plasma on Vero cells. Vaccine virus was also recovered from buffy coat material from one of those vaccinees and from one additional vaccinee. Through RNA sequencing of MP-12 isolates, we found no reversions of amino acids to those of the parent virulent virus (strain ZH548). Five years after a single dose of RVF MP-12 vaccine, 8 of 9 vaccinees (89%) maintained a PRNT80 ≥ 1:20. These findings support the continued development of RVF MP-12 as a countermeasure against RVF virus in humans.

Rift Valley fever vaccines: an overview of the safety and efficacy of the live-attenuated MP-12 vaccine candidate

“…The MP-12 vaccine lot has been used for various vaccine safety and efficacy studies using different animal models, including mice, sheep (adult, pregnant ewes, young, and newborn lambs), cattle (adult, lactating cows, pregnant cows, newborn, and young calves), and rhesus macaques [18,20–32]. The MP-12 vaccine is an Investigational New Drug to be tested in humans, and its safety and immunogenicity have been tested in clinical trials, including healthy adults [33,34]. In 2013, the MP-12 vaccine was conditionally licensed to Zoetis Inc. for animal vaccination in the U.S. without specific descriptions in the issuance of a conditional license in terms of applied animal species, pregnancy, or age [35], and new vaccine master seed has been generated accordingly by additional amplification of TSI-GSD-223 in MRC-5 cells [27,36].…”

“…A total of 19 volunteers were vaccinated with the MP-12 vaccine (1×10 5 pfu, i.m.) and 18 (95%) had increased PRNT 80 titers of ≥ 1:20 by 28 dpv, and maintained 1:20 or higher titers for 12 months afterwards [34]. Follow-up evaluation of those volunteers showed that eight of nine tested sera still maintained neutralizing antibodies of ≥ 1:20 at five years post vaccination.…”

“…High throughput sequencing of the MP-12 vaccine lot (TSI-GSD-223) did not detect any parental ZH548 strain sequence at those four ts mutation sites [19]. Furthermore, viral isolates from MP-12 vaccinees during a clinical trial did not show any reversion mutations at any of the key mutation sites [34]. Overall, it is unlikely that a highly pathogenic RVFV strain can be formed from the MP-12 vaccine strain during the manufacturing of MP-12 vaccine or during the limited viral replication in vivo .…”

UK vaccines network: Mapping priority pathogens of epidemic potential and vaccine pipeline developments

“…Phase 2 trials have also been completed for vaccines against Chikungunya and Rift Valley Fever virus, although the Chikungunya vaccines are likely to reach the market faster since their development is being driven by commercial organisations. The RVFV vaccines were tested by the US Army and therefore may not be immediately available for the general population [28]. It is interesting to note that new RVFV vaccines are being developed for animal vaccination but to date there have been no trials of these vaccines in humans [29][30][31].…”

Vaccines for emerging pathogens: prospects for licensure

“…In the United Kingdom, and subsequent to the Ebola outbreak in West Africa, vaccine networks for human and veterinary vaccines have formed to prioritize vaccine efforts in these respective contexts [61], while the Department of Health, together with Innovate UK, has supported R&D of vaccine candidates for the prioritized pathogens [62]. As a result of these global initiatives, a number of candidate vaccines are being developed for emerging bacterial and viral pathogens, examples of which, although by no means exhaustive, are cited here [63][64][65][66][67][68][69][70][71][72][73][74]. WHO reports ongoing global vaccine R&D efforts [75] and also tracks the progress of clinical trials for emerging pathogens [76].…”