Efficacy and Safety Studies of a Recombinant Chimeric Respiratory Syncytial Virus FG Glycoprotein Vaccine in Cotton Rats

Abstract

Several formulations of a recombinant chimeric respiratory syncytial virus (RSV) vaccine consisting of the extramembrane domains of the F and G glycoproteins (FG) were tested in cotton rats to evaluate efficacy and safety. The FG vaccine was highly immunogenic, providing nearly complete resistance to pulmonary infection at doses as low as 25 ng in spite of inducing relatively low levels of serum neutralizing antibody at low vaccine doses. Upon RSV challenge animals primed with FG vaccine showed quite mild alveolitis and interstitial pneumonitis, which were eliminated by the addition of monophosphoryl lipid A to the formulation.The quest for a safe and effective vaccine against respiratory syncytial virus (RSV), now in its fourth decade, has alternately focused on nonreplicating and replicating candidate vaccines (reviewed in reference 12). The first vaccine to enter clinical trials contained formalin-inactivated RSV (FI-RSV). The vaccine was moderately antigenic, but the unexpected development of enhanced pulmonary disease in vaccinees subsequently undergoing natural RSV infection brought the trials to an abrupt halt (6, 13, 17, 19) and raised general questions concerning the safety of nonreplicating RSV vaccines that persist to this day. Indeed, since 1965 no nonreplicating RSV candidate vaccine has been permitted to be tested in immunologically naive infants, a likely target population. By contrast, replicating virus RSV vaccines have been plagued by genetic instability (10, 18,36), residual virulence (18), inadequate antigenicity (35,36), and the blocking effect of maternal antibody (3,26). Even if such obstacles could be overcome, a heat-stable vaccine would still have the advantage of applicability in developing countries (and even some areas of developed countries) where the "cold chain" essential for replicating viral vaccines cannot be assured. Several nonviral RSV vaccines have also been evaluated, including a DNA plasmid that expresses gene products intracellularly (20) and a live Staphylococcus displaying G glycoprotein peptides (5), which replicates extracellularly.A number of nonreplicating RSV vaccines are under development. These include chromatographically purified F glycoprotein (15, 24, 31), recombinant chimeric F and G glycoproteins (23), recombinant chimeric RSV-F-parainfluenza virus-HN glycoproteins (11), recombinant F glycoprotein (14) and recombinant G glycoprotein (25), or a synthetic G glycoprotein peptide (1).We tested a recombinant chimeric vaccine consisting of the extramembrane domains of the F and G viral glycoproteins. Various formulations, differing in expression systems and adjuvants, have been tested using cotton rats, and questions of efficacy and safety are addressed. A similar but not identical vaccine has been tested previously (4) but was shown to cause enhanced pulmonary disease upon live virus challenge (7). The same vaccine was previously tested in mice (23), which do not develop lesions typical of enhanced disease as do cotton rats. MATERIALS AND METHODSFG antigen. The...

Immunoprotective Activity and Safety of a RespiratorySyncytial Virus Vaccine: Mucosal Delivery of Fusion Glycoprotein with aCpG OligodeoxynucleotideAdjuvant

“…Such pathology was first appreciated during clinical trials of a formalin-inactivated vaccine, which resulted in severely enhanced (and in some cases fatal) disease (2,6,12,13). The histopathologic changes seen in the two children who died in that study (23) are similar to those observed with other nonreplicating RSV vaccines (19,22), as well as those in the present report. Lingering concerns that novel nonreplicating RSV vaccines might also predispose to the development of proinflammatory immune-mediated lung pathology have cast a persistent shadow over RSV vaccinology.…”

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

“…However, enhancement was also found with the parainfluenza 3 vaccine inactivated by ultraviolet light [16]. Additionally, minor degrees of enhancement have been noted with a recombinant chimeric RSV FG glycoprotein and that effect was eliminated by a monophosphoral lipid A adjuvant which also reduces pathology of FI-RSV vaccine enhanced disease [19]. This adjuvant also had a dramatic effect in reducing both Th-1 and Th-2-type cytokines in a model of FI-RSV vaccine enhancement in cotton rats [4].…”

“…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]. The cotton rat has also been used extensively to study hRSV especially in the area of enhanced pulmonary disease caused by some vaccine candidates for hRSV [19][20][21][22].…”

Challenges in developing a pediatric RSV vaccine

“…131 Several RSV F, G and chimeric FG subunit vaccines have shown to be effective in rodent models, though only RSV F subunit vaccines have been extensively tested in humans. 51,81,132,133 Purified RSV F glycoproteins (PFPs) adjuvanted with alum were shown to exhibit an acceptable safety profile and to be immunogenic as measured by a ≥four-fold rise in RSV neutralizing antibody titers. PFP vaccines were generally more immunogenic in seropositive children than adults.…”