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

Naunyn-Schmiedeberg's Archives of Pharmacology, Dec 2012

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.

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

Clarisse Lorin 0 2 Lawrence Segal 0 2 Johann Mols 0 2 Danielle Morelle 0 2 Patricia Bourguignon 0 2 Olga Rovira 0 2 Pascal Mettens 0 2 Jrmy Silvano 0 2 Nicolas Dumey 0 2 Frdrick Le Goff 0 2 Marguerite Koutsoukos 0 2 Gerald Voss 0 2 Frdric Tangy 0 2 0 J. Silvano Centre International de Toxicologie , Evreux, France 1 ) GlaxoSmithKline Vaccines, Rue Fleming 20, 1300 Wavre, Belgium 2 F. Tangy Unit de Gnomique Virale et Vaccination, Institut Pasteur , CNRS URA-3015, Paris, France 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 C. Lorin and L. Segal contributed equally to this study. - The development of a safe and effective prophylactic vaccine against human immunodeficiency virus type I (HIV-1) is a global health priority. During the past two decades, significant efforts have been made to develop such a vaccine. Among the few candidate HIV-1 vaccines tested in large Phase IIb or III clinical trials, only the RV144 trial, evaluating a recombinant canarypox vector prime and HIV-1 gp120 protein boost, showed a modest efficacy (31 %) against HIV-1 acquisition (reviewed by McElrath and Haynes 2010; McMichael et al. 2010). Although ultimately, a preventive vaccine against HIV-1 inducing sterile immunity would be optimal, vaccines that would reduce viral load and disease progression by induction of strong and polyfunctional T cell responses should also prove beneficial (McMichael et al. 2010). Live attenuated measles virus (MV) vaccine strains, such as the widely used and strongly immunogenic Schwarz strain (Griffin 2007), are replicating RNA viruses (Paramyxoviridae family), capable of inducing long-lived antibody and memory T cell responses (Ovsyannikova et al. 2003; Vandermeulen et al. 2007). Besides being highly efficacious, these vaccines are also recognized as safe (WHO 2009), as MV replicates in the cytoplasm and does not integrate into the host cell genome. Moreover, reversion of the vaccine genome into a pathogenic form has never been observed. The experience accumulated with these vaccines in the past 50 years, and their capacity to induce both CD4+ and CD8+ T cells, render recombinant MV vectors an attractive platform for vaccines aimed to induce T cell responses specific for the HIV-1 transgene. For several of these vaccines expressing HIV-1 antigens, the immunogenicity has been preclinically demonstrated (Combredet et al. 2003; Guerbois et al. 2009; Liniger et al. 2009; Lorin et al. 2004). We constructed the HIV-1 vaccine candidate MV1-F4, using an in vivo replication-competent MV vector (Combredet et al. 2003) derived from the Schwarz vaccine strain, to generate recombinant MV expressing the F4 antigen. F4 is a fusion protein comprising the clade B viral antigens p17, p24, reverse transcriptase and the regulatory protein Nef. Combined with AS01 (a liposome-based Adjuvant System containing 3-O-desacyl-4-monophosphoryl lipid A (MPL) and QS21; Garon et al. 2007), this F4 antigen was shown to induce potent polyfunctional CD4+ T cell responses in HIVseronegative volunteers (Van Braeckel et al. 2011). We conducted a study of the biodistribution, shedding and single- and repeated-dose toxicity of one or three intramuscular (IM) immunizations with MV1-F4 in cynomolgus macaques. The potential intrinsic toxicity of MV1-F4 was studied, as well as the potential immune-mediated toxicity resulting from the host response to the vaccine. The resulting toxicity and biodistribution profiles, including any target organs identified, could be used to guide clinical safety monitoring, while the shedding profile is crucial for determining the potential of infectious viral dissemination by future vaccine recipients, and thus of person-to-person transmission of the virus. The biodistribution, shedding and toxicity profiles of the MV1-F4 vaccine were compared to those of either the reference vaccine (the live attenuated monovalent Schwarz MV vaccine Rouvax), or saline. Humans are the natural hosts of MV. Measles pathogenesis has traditionally been studied in non-human primates as no suitable alternative models exist. Live attenuated MV vaccines are generally non-infectious in rodents, except for cotton rats (in which MV replication is restricted to the lungs) and transgenic mice (which reproduce only limited aspects o (...truncated)


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Clarisse Lorin, Lawrence Segal, Johann Mols, Danielle Morelle, Patricia Bourguignon, Olga Rovira, Pascal Mettens, Jérémy Silvano, Nicolas Dumey, Frédérick Le Goff, Marguerite Koutsoukos, Gerald Voss, Frédéric Tangy. Toxicology, biodistribution and shedding profile of a recombinant measles vaccine vector expressing HIV-1 antigens, in cynomolgus macaques, Naunyn-Schmiedeberg's Archives of Pharmacology, 2012, pp. 1211-1225, Volume 385, Issue 12, DOI: 10.1007/s00210-012-0793-4