Safety and immunogenicity of a mutagenized, live attenuated Rift Valley fever vaccine, MP-12, in a Phase 1 dose escalation and route comparison study in humans

Abstract

Rift Valley fever (RVF) poses a risk as a potential agent in bioterrorism or agroterrorism. A live attenuated RVF vaccine (RVF MP-12) has been shown to be safe and protective in animals and showed promise in two initial clinical trials. In the present study, healthy adult human volunteers (N=56) received a single injection of (a) RVF MP-12, administered subcutaneously (SQ) at a concentration of 10 4.7 plaque-forming units (pfu) (SQ Group); (b) RVF MP-12, administered intramuscularly (IM) at 10 3.4 pfu (IM Group 1); (c) RVF MP-12, administered IM at 10 4.4 pfu (IM Group 2); or (d) saline (Placebo Group). The vaccine was well tolerated by volunteers in all dose and route groups. Infrequent and minor adverse events were seen among recipients of both placebo and RVF MP-12. One subject had viremia detectable by direct plaque assay, and six subjects from IM Group 2 had transient low-titer viremia detectable only by nucleic acid amplification. Of the 43 vaccine recipients, 40 (93%) achieved neutralizing antibodies (measured as an 80% plaque reduction neutralization titer [PRNT80]) as well as RVF-specific IgM and IgG. The highest peak geometric mean PRNT80 titers were observed in IM Group 2. Of 34 RVF MP-12 recipients available for testing 1 year following inoculation, 28 (82%) remained seropositive (PRNT80  1:20); this included 20 of 23 vaccinees (87%) from IM Group 2. The live attenuated RVF MP-12 vaccine was safe and immunogenic at the doses and routes studied. Given the need for an effective vaccine against RVF virus, further evaluation in humans is warranted.

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].…”

“…In the initial human trial, three out of four volunteers administered with the MP-12 vaccine (10 4.4 pfu dose, s.c.) developed neutralizing antibodies, whereas all four showed transient mild to moderate elevation of serum alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) [33]. In a subsequent dose escalation study, 22 humans were administered with the MP-12 vaccine (either 10 4.4 , 10 3.4 , 10 2.4 , or 10 1.4 pfu dose, s.c.) [33].…”

“…In a subsequent dose escalation study, 22 humans were administered with the MP-12 vaccine (either 10 4.4 , 10 3.4 , 10 2.4 , or 10 1.4 pfu dose, s.c.) [33]. Within the 10 4.4 pfu dose group, seroconversion (positive for IgM or IgG via either PRNT 50 or PRNT 80 , or ELISA) occurred in two of four individuals, in addition to injection site tenderness (3 of 4), severe AST elevation (1 of 4), or elevated creatine phosphokinase (CPK) (3 of 4).…”

“…route (10 3.4 pfu, n = 6, or 10 4.4 pfu, n = 27) was performed [33]. Overall, 93% of subjects (40 of 43) showed an increase in neutralizing antibody titers (PRNT 80 ≥20) from 14 to 21 dpv.…”

Rift Valley Fever

“…85 Despite these potential limitations, MP-12 is still being pursued as a human vaccine to this day. 86–88 …”