13-valent pneumococcal conjugate vaccine immune sera protects against pneumococcal serotype 1, 3, and 5 bacteremia in a neonatal rat challenge model.

PCV7 was first licensed in the United States in 2000 based on clinical efficacy studies. Since the introduction, PCV7 has demonstrated protective effectiveness for each of the vaccine serotypes. More recently, PCV13 has been licensed in more than 60 countries based on serological noninferiority to PCV7 for the shared serotypes and noninferiority to the least immunogenic serotypes of PCV7 for the additional 6 serotypes in PCV13. To evaluate whether the functional antibody responses to serotypes 1, 3, and 5 were sufficient to protect animals challenged with virulent strains of these serotypes, rhesus macaques were immunized with three clinical doses of PCV13. The macaques mounted robust anti-capsular polysaccharide IgG and opsonophagocytic killing (OPA) responses to each serotype contained in the vaccine. Pooled pre-immunization sera and post-immunization serum pools were tested in a neonatal rat bacteremia model. Passive transfer of pooled post-immunization sera, but not pre-immunization sera, protected neonatal rats from lethal IP challenge with serotype 1, 3, or 5 strains. The functional activity of PCV13 immune sera against a virulent type 3 strain was further evaluated using sera from human children immunized with 4 doses of PCV7 or PCV13. Pooled sera from children immunized with PCV13, but not pooled sera from children immunized with PCV7, which does not contain the serotype 3 polysaccharide conjugate, protected neonatal rats from lethal IP challenge with a highly encapsulated and virulent serotype 3 strain. These data suggest that PCV13 will provide protection against pneumococcal serotype 1, 3, and 5 disease in human populations, even at relatively low OPA titers.

Evaluation of neurovirulence and biodistribution of Venezuelan equine encephalitis replicon particles expressing herpes simplex virus type 2 glycoprotein D.

The safety of a propagation-defective Venezuelan equine encephalitis virus (VEEV) replicon particle vaccine was examined in mice. After intracranial inoculation we observed approximately 5% body weight loss, modest inflammatory changes in the brain, genome replication, and foreign gene expression. These changes were transient and significantly less severe than those caused by TC-83, a live-attenuated vaccinal strain of VEEV that has been safely used to immunize military personnel and laboratory workers. Replicon particles injected intramuscularly or intravenously were detected at limited sites 3 days post-administration, and were undetectable by day 22. There was no evidence of dissemination to spinal cord or brain after systemic administration. These results demonstrate that propagation-defective VEEV replicon particles are minimally neurovirulent and lack neuroinvasive potential.

Recombinant vesicular stomatitis virus vectors expressing herpes simplex virus type 2 gD elicit robust CD4+ Th1 immune responses and are protective in mouse and guinea pig models of vaginal challenge.

Recombinant vesicular stomatitis virus (rVSV) vectors offer an attractive approach for the induction of robust cellular and humoral immune responses directed against human pathogen target antigens. We evaluated rVSV vectors expressing full-length glycoprotein D (gD) from herpes simplex virus type 2 (HSV-2) in mice and guinea pigs for immunogenicity and protective efficacy against genital challenge with wild-type HSV-2. Robust Th1-polarized anti-gD immune responses were demonstrated in the murine model as measured by induction of gD-specific cytotoxic T lymphocytes and increased gamma interferon expression. The isotype makeup of the serum anti-gD immunoglobulin G (IgG) response was consistent with the presence of a Th1-CD4+ anti-gD response, characterized by a high IgG2a/IgG1 IgG subclass ratio. Functional anti-HSV-2 neutralizing serum antibody responses were readily demonstrated in both guinea pigs and mice that had been immunized with rVSV-gD vaccines. Furthermore, guinea pigs and mice were prophylactically protected from genital challenge with high doses of wild-type HSV-2. In addition, guinea pigs were highly protected against the establishment of latent infection as evidenced by low or absent HSV-2 genome copies in dorsal root ganglia after virus challenge. In summary, rVSV-gD vectors were successfully used to elicit potent anti-gD Th1-like cellular and humoral immune responses that were protective against HSV-2 disease in guinea pigs and mice.

Herpes simplex virus type 2 UL24 gene is a virulence determinant in murine and guinea pig disease models.

A herpes simplex virus type 2 (HSV-2) UL24 beta-glucuronidase (UL24-betagluc) insertion mutant was derived from HSV-2 strain 186 via standard marker transfer techniques. Cell monolayers infected with UL24-betagluc yielded cytopathic effect with syncytium formation. UL24-betagluc replicated to wild-type viral titers in three different cell lines. UL24-betagluc was not virulent after intravaginal inoculation of BALB/c mice in that all inoculated animals survived doses up to 400 times the 50% lethal dose (LD50) of the parental virus. Furthermore, few UL24-betagluc-inoculated mice developed any vaginal lesions. Intravaginal inoculation of guinea pigs with UL24-betagluc at a dose equivalent to the LD50 of parental virus (approximately 5 x 10(3) PFU) was not lethal (10/10 animals survived). Although genital lesions developed in some UL24-betagluc-inoculated guinea pigs, both the overall number of lesions and the severity of disease were far less than that observed for animals infected with parental strain 186.