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We compared the efficacy of immunization with either simian immunodeficiency virus (SIV) Env glycoprotein (Env), Env plus Gag proteins (Gag-Env), or whole inactivated virus (WIV), with or without recombinant live vaccinia vector (VV) priming, in protecting 23 rhesus macaques (six vaccine and two control groups) from challenge with SIVmac251 clone BK28. Vaccination elicited high titers of syncytium-inhibiting and anti-Env (gp120/gpl60) antibodies in all vaccinated macaques and anti-Gag (p27) antibodies in groups immunized with WIV or Gag-Env. Only WIV-immunized macaques developed anticell (HuT78) antibodies. After homologous low-dose intravenous virus challenge, we used frequency of virus isolation, provirus burden, and change in antibody titers to define four levels of resistance to SIV infection as follows. (i) No infection ("sterilizing" immunity) was induced only in WIV-immunized animals. (ii) Abortive infection (strong immunity) was defined when virus or provirus were detected early in the postchallenge period but not thereafter and no evidence of virus or provirus was detected in terminal tissues. This response was observed in two animals (one W-Env and one Gag-Env). (iii) Suppression of infection (incomplete or partial immunity) described a gradient of virus suppression manifested by termination of viremia, declining postchallenge antibody titers, and low levels (composite mean = 9.1 copies per 106 cells) of provirus detectable in peripheral blood mononuclear cells or lymphoid tissues at termination (40 weeks postchallenge). This response occurred in the majority (8 of 12) of subunit-vaccinated animals. (iv) Active infection (no immunity) was characterized by persistent virus isolation from blood mononuclear cells, increasing viral antibody titers postchallenge, and high levels (composite mean = 198 copies per 106 cells) of provirus in terminal tissues and blood. Active infection developed in all controls and two of three W-Gag-Env-immunized animals. The results of this study restate the protective effect of inactivated whole virus vaccines produced in heterologous cells but more importantly demonstrate that a gradient of suppression of challenge virus growth, reflecting partial resistance to SIV infection, is induced by subunit vaccination. The latter finding may be pertinent to studies with human immunodeficiency virus vaccines, in which it is plausible that vaccination may elicit significant suppression of virus infection and pathogenicity rather than sterilizing immunity.

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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...