Identification of small-animal and primate models for evaluation of vaccine candidates for human metapneumovirus (hMPV) and implications for hMPV vaccine design

Abstract

Human metapneumovirus (hMPV), a recently identified paramyxovirus, is the causative agent of respiratory tract disease in young children. Epidemiological studies have established the presence of hMPV in retrospective as well as current clinical samples in Europe, USA, Canada, Hong Kong and Australia. The hMPV disease incidence rate varied from 7 to 12 %. This rate of disease attack places hMPV in severity between respiratory syncytial virus and human parainfluenza virus type 3, two common respiratory pathogens of young children, the elderly and immunosuppressed individuals. To evaluate the effectiveness and safety of future hMPV antiviral drugs, therapeutic and prophylactic monoclonal antibodies (mAbs), and vaccine candidates, it was necessary to identify small-animal and primate models that efficiently supported hMPV replication in the respiratory tract and produced neutralizing serum antibodies, commonly a clinical correlate of protection in humans. In this study, various rodents (mice, cotton rats, hamsters and ferrets) and two primate species, rhesus macaques and African green monkeys (AGMs), were evaluated for hMPV replication in the respiratory tract. The results showed that hamsters, ferrets and AGMs supported hMPV replication efficiently and produced high levels of hMPV-neutralizing antibody titres. Hamsters vaccinated with subgroup A hMPV were protected from challenge with subgroup A or subgroup B hMPV, which has implications for hMPV vaccine design. Although these animal models do not mimic human hMPV disease signs, they will nevertheless be invaluable for the future evaluation of hMPV antivirals, mAbs and vaccines.

Pathogenesis of Human Metapneumovirus Lung Infection in BALB/c Mice and Cotton Rats

“…For instance, MacPhail et al observed low hMPV titers in the lungs of BALB/c mice and cotton rats, following an intranasal challenge of 10 6 PFU (i.e., 10 2.4 and Ͻ10 1.8 PFU/g of lung, respectively, on day 4 postinfection) (28). Furthermore, no clinical signs were observed in those animals.…”

“…The two paramyxoviruses have been associated with bronchiolitis and pneumonia in young children (9,17,23,48). Although some primates are permissible to hMPV (26,28,42) and hRSV (11) infections, we selected to study BALB/c mice and cotton rats as possible experimental models for hMPV infection because those small animals are considered useful and practical models for characterizing the pathogenesis of hRSV infection and for evaluating therapeutic and prophylactic approaches (7, 11, 12, 19, 22, 24, 33, 38, 39, 41, 45, 46, 50).…”

“…Viral replication has been found in the respiratory tract of experimentally infected chimpanzees and monkeys (cynomolgus monkeys, rhesus macaques, and African green monkeys) and was associated with mild upper respiratory tract signs in some of these animals (26,28,42). Some groups have also shown that hMPV can replicate in the lungs of hamsters without the appearance of recognizable clinical signs (28,37,40). Recently, Alvarez et al have reported efficient hMPV replication in lungs of BALB/c mice associated with transient weight loss (1).…”

Human metapneumovirus: Enhanced pulmonary disease in cotton rats immunized with formalin-inactivated virus vaccine and challenged

“…Its ability to co-infect with other respiratory infectious agents, including RSV and pneumococci [14,27], combined with its relatively slow replication in cell culture likely accounted for its ability to escape isolation until 2001. Various animal models have been utilized to study hMPV infection including mice, hamsters, and several species of primates [10,12,13,23]. Recent studies indicate that infection of cotton rats with hMPV is associated with efficient viral replication in the lung and reproducible pulmonary pathology [10,28,30].…”

Parainfluenza Virus Type 3 Expressing the Native or Soluble Fusion (F) Protein of Respiratory Syncytial Virus (RSV) Confers Protection from RSV Infection in African Green Monkeys

“…The replication properties of hMPV in the respiratory tract of AGMs were described elsewhere (26). The daily mean replication titers showed that b/h PIV3 RSV F2 and b/h PIV3/sol RSV F2 achieved peak virus titers of ϳ5 log 10 in the URT on day 4 postimmunization (Fig.…”