Toxicology, biodistribution and shedding profile of a recombinant measles vaccine vector expressing HIV-1 antigens, in cynomolgus macaques

Abstract

As a new human immunodeficiency virus type 1 (HIV-1) vaccine approach, the live-attenuated measles virus (MV) Schwarz vaccine strain was genetically engineered to express the F4 antigen (MV1-F4). F4 is a fusion protein comprising HIV-1 antigens p17 and p24, reverse transcriptase and Nef. This study assessed the toxicity, biodistribution and shedding profiles of MV1-F4. Cynomolgus macaques were intramuscularly immunized one or three times with the highest dose of MV1-F4 intended for clinical use, the reference (Schwarz) measles vaccine or saline, and monitored clinically for 11 or 85 days. Toxicological parameters included local and systemic clinical signs, organ weights, haematology, clinical and gross pathology and histopathology. Both vaccines were well tolerated, with no morbidity, clinical signs or gross pathological findings observed. Mean spleen weights were increased after three doses of either vaccine, which corresponded with increased numbers and/or sizes of germinal centers. This was likely a result of the immune response to the vaccines. Either vaccine virus replicated preferentially in secondary lymphoid organs and to a lesser extent in epithelium-rich tissues (e.g., intestine, urinary bladder and trachea) and the liver. At the expected peak of viremia, viral RNA was detected in some biological fluid samples from few animals immunized with either vaccine, but none of these samples contained infectious virus. In conclusion, no shedding of infectious viral particles was identified in cynomolgus monkeys after injection of MV1-F4 or Schwarz measles vaccines. Furthermore, no toxic effect in relation to the MV vaccination was found with these vaccines in this study.

Fig. 1

Anti-MV antibody levels and seroconversion rates. Serum levels of anti-MV antibodies were measured prior to or after injection of MV1-F4, Rouvax or saline. Antibody levels were expressed as the ratio between the optical density (OD) at 490 and at 620 nm. Animals were considered to be responders if the absorbance exceeded the cut-off value, for a serum dilution of 1:500. Each line represents one monkey. Plain and open symbols represent male and female monkeys, respectively. a Young animals (N = 6/group) were immunized at day 1 and sacrificed at day 11 (groups 1, 2 and 3). Blood samples were taken at days 0 and 11. b Young animals (N = 6/group) were immunized at days 1, 29 and 57, and sacrificed at day 85 (groups 4, 5 and 6). Blood samples were taken at days 0, 11, 29, 56, 67 and 85. c Sexually mature animals (N = 3/group) were immunized at days 1, 29 and 57 (groups 7 and 8). Blood samples were taken at days 0, 11, 29, 56, 67 and 85