Toxicology, biodistribution and shedding profile of a recombinant measles vaccine vector expressing HIV-1 antigens, in cynomolgus macaques
Clarisse Lorin
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Lawrence Segal
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Johann Mols
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Danielle Morelle
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Patricia Bourguignon
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Olga Rovira
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Pascal Mettens
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Jrmy Silvano
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Nicolas Dumey
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Frdrick Le Goff
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Marguerite Koutsoukos
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Gerald Voss
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Frdric Tangy
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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.
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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)