Crowe, JE Jr, Collins, PL, London, WT, Chanock, RM and Murphy, BR. A comparison in chimpanzees of the immunogenicity and efficacy of live attenuated respiratory syncytial virus (RSV) temperature-sensitive mutant vaccines and vaccinia virus recombinants that express the surface glycoproteins of RSV. Vaccine 11: 1395-1404
Respiratory syncytial virus (RSV) is the most common cause of viral bronchiolitis and pneumonia in children. The present study compares the level of attenuation, genetic stability and efficacy of three conditional-lethal temperature-sensitive (ts) mutants of the RSV A2 wild-type virus, designated ts-1, ts-1-NG1, and ts-4, in seronegative chimpanzees and also compares their efficacy with that of vaccinia virus recombinants that express the surface glycoproteins of RSV. Each of the ts mutants was highly attenuated in the lower respiratory tract, but still retained the capacity to induce significant rhinorrhoea. Each of the three ts mutants underwent partial reversion to a non-ts (ts+) phenotype during replication in a minority of the chimpanzees. The ts+ virus present in the upper respiratory tract of the chimpanzees did not spread to the lower respiratory tract and represented only a minority fraction of the virus present in the nasopharyngeal swab specimens. The ts mutants were highly immunogenic and provided resistance that effectively restricted RSV replication following virus challenge. In contrast, the vaccinia-RSV recombinants were less immunogenic. They protected the lungs of two of four chimpanzees challenged with RSV, but failed to protect the upper respiratory tract. The chimpanzee can serve as a model for the rapid evaluation of further attenuated live RSV vaccines.
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"Preclinical studies with many non-replicating RSV vaccine candidates have stalled because of concerns about enhanced disease in animal models. Immunization with live attenuated RSV strains or with other viruses that express RSV antigens does not result in enhanced disease in NHP , although in some instances, immunization of mice with chimeric viruses that express RSV antigens can result in enhanced disease . However, no live vaccine has been approved for RSV or MPV. "
[Show abstract][Hide abstract] ABSTRACT: Human respiratory syncytial virus (hRSV) and human metapneumovirus (hMPV) are major causes of illness among children, the elderly, and the immunocompromised. No vaccine has been licensed for protection against either of these viruses. We tested the ability of two Venezuelan equine encephalitis virus-based viral replicon particle (VEE-VRP) vaccines that express the hRSV or hMPV fusion (F) protein to confer protection against hRSV or hMPV in African green monkeys. Animals immunized with VEE-VRP vaccines developed RSV or MPV F-specific antibodies and serum neutralizing activity. Compared to control animals, immunized animals were better able to control viral load in the respiratory mucosa following challenge and had lower levels of viral genome in nasopharyngeal and bronchoalveolar lavage fluids. The high level of immunogenicity and protective efficacy induced by these vaccine candidates in nonhuman primates suggest that they hold promise for further development.
[Show abstract][Hide abstract] ABSTRACT: RSV and PIV3 are responsible for about 30% of severe viral respiratory tract disease leading to hospitalization of infants and children. For this reason, there is a need to develop vaccines effective against these viruses. Since these viruses cause severe disease in early infancy, vaccines must be effective in the presence of maternal antibody. Currently, several strategies for immunization against these viruses are being explored including peptide vaccines, subunit vaccines, vectored vaccines (e.g., vaccinia-RSV or adenovirus-RSV recombinants), and live attenuated virus vaccines. The current status of these approaches is reviewed. In addition, the immunologic basis for the disease potentiation seen in vaccinees immunized with formalin-inactivated RSV during subsequent RSV infection is reviewed. The efficacy of immunization in the presence of maternal antibody is discussed. Much progress for a RSV and PIV3 vaccine has been made and successful immunization against each of these pathogens should be achieved within this decade.
[Show abstract][Hide abstract] ABSTRACT: A cold-passaged RSV mutant, designated cp-RSV, which acquired host range mutations during 52 passages at low temperature in bovine tissue culture, was completely attenuated for seropositive adults and children but retained the capacity to cause upper respiratory disease in seronegative infants. We sought to introduce additional attenuating mutations, such as temperature-sensitive (ts) and small-plaque (sp) mutations, into the cp-RSV mutant, which is a ts + virus, in order to generate a mutant which would be satisfactorily attenuated in seronegative infants and young children. Nine mutants of cp-RSV, which had acquired either the ts or small-plaque sp phenotype, were generated by chemical mutagenesis with 5-fluorouracil. The two ts mutants with the lowest in vitro shut-off temperature, namely the cpts-248 (38°C) and cpts-530 (39°C) mutants, were the most restricted of the nine cp-RSV mutant progeny tested for efficiency of replication in Balb/c mice. In seronegative chimpanzees, the cpts-248 mutant replicated fourfold less efficiently in the nasopharynx and caused significantly less rhinorrhoea than its cp-RSV parent. The cpts-248 mutant virus, like its cp-RSV parent, was 1000-fold restricted in replication in the trachea compared with wild-type RSV. Previously, another candidate RSV live attenuated vaccine strain, a mutant designated ts-1, exhibited some instability of its ts phenotype following replication in susceptible humans or chimpanzees. Hence, we sought cp-RSV ts progeny that exhibited a greater degree of stability of the ts phenotype than the prototype ts-1 mutant. The cpts-248 and cpts-530 progeny viruses exhibited a greater degree of stability of the ts phenotype in nude mice than the ts-1 virus, and in chimpanzees, the former mutant also exhibited a greater stability of its ts phenotype than ts-1. The cpts-248 mutant was immunogenic and induced a high level of resistance in chimpanzees to subsequent challenge with wild-type RSV. The cpts-248 mutant therefore exhibits a set of properties that make it a promising vaccine candidate. These desirable properties of cpts-248 suggest that the mutant should be tested in humans for its suitability in immunoprophylaxis.