T-cell immunotherapy that takes advantage of Epstein-Barr virus (EBV)-

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The spectrum of immunogenic epitopes presented by the H2-IA b MHC class II molecule to CD4 ؉ T cells has been defined for two different (clade B and clade D) HIV envelope (gp140) glycoproteins. Hybridoma T cell lines were generated from mice immunized by a sequential prime and boost regime with DNA, recombinant vaccinia viruses, and protein. The epitopes recognized by reactive T cell hybridomas then were characterized with overlapping peptides synthesized to span the entire gp140 sequence. Evidence of clonality also was assessed with antibodies to T cell receptor V␣ and V␤ chains. A total of 80 unique clonotypes were characterized from six individual mice. Immunogenic peptides were identified within only four regions of the HIV envelope. These epitope hotspots comprised relatively short sequences (Ϸ20-80 aa in length) that were generally bordered by regions of heavy glycosylation. Analysis in the context of the gp120 crystal structure showed a pattern of uniform distribution to exposed, nonhelical strands of the protein. A likely explanation is that the physical location of the peptide within the native protein leads to differential antigen processing and consequent epitope selection.T he primary role of any vaccine is to generate sustained immune memory to antigenic epitopes that are expressed on, or by, the pathogen in question. Vaccines designed to prevent the development of virus-induced pathology must promote the clonal expansion of CD4 ϩ T cells specific for those complexes of nonself peptide and self MHC class II glycoprotein that will be encountered again as a consequence of natural virus challenge. Experiments in a variety of mouse model systems have established that the virus-specific CD4 ϩ (T h ) subset functions both to enhance antibody production by cognate interaction with B cells (1, 2) and to promote the development of effector CD8 ϩ T cells (3, 4). Studies of readily eliminated viruses further indicate that the development of long-term memory in both lymphocyte compartments depends substantially on a concurrent T h response (5), and CD8 ϩ T cell-mediated control of persistent infections requires the continued presence of virus-specific CD4 ϩ T cells (6, 7). This CD4 ϩ T h for the CD8 ϩ subset is thought to operate via the intermediary of the activated dendritic cell (8).In some infections, particularly with the large DNA viruses, INF-␥-producing CD4 ϩ T cells are also important effectors of immunity (9-11). An ongoing CD4 ϩ T cell response also is thought to be important for the CD8 ϩ T cell-mediated control of HIV infection (12). Effective priming of the CD4 ϩ T cell response would thus seem to be a priority for any HIV vaccine.What is known about the antigenic epitopes recognized by HIV-specific CD4 ϩ T cells? Previous studies have sought to characterize immunogenic peptides from the HIV envelope (env) protein (13-20) for a variety of mammalian species expressing a spectrum of MHC class II phenotypes. Much of the available information was generated by scoring heterogeneous CD4 ϩ T cell respons...

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Group B Streptococcus (GBS) is a leading cause of neonatal sepsis in developed countries. Its burden in the developing world is less clear. Studies reporting neonatal GBS disease incidence from developing countries were identified from 5 literature databases. Studies were assessed with respect to case finding and culture methods. Only 20 studies were identified. The GBS incidence ranged 0-3.06 per 1000 live births with variation within and between geographic regions. All but 1 study identified GBS cases within a hospital setting, despite the potential for births in the community. Possible case under-ascertainment was only discussed in 2 studies. A higher GBS incidence was reported when using automated culture methods. Prospective, population-based surveillance is urgently needed in developing countries to provide an accurate assessment of the neonatal GBS disease burden. This will be crucial for the design of interventions, including novel vaccines, and the understanding of their potential to impact mortality from neonatal sepsis.

SummaryBackgroundNeonates born to women infected with HIV are at increased risk for invasive group B streptococcus (GBS) disease. We aimed to compare safety and immunogenicity of trivalent glycoconjugate GBS vaccine in pregnant women with and without HIV in Malawi and South Africa.MethodsIn our non-randomised phase 2, open-label, multicentre study, we recruited pregnant women attending two antenatal clinics, one in Blantyre, Malawi, and one in Soweto, Johannesburg, South Africa. Participants were divided into three groups on the basis of their HIV infection status (no infection, infection and high CD4 cell count [>350 cells per μL], and infection and low CD4 cell count [>50 to ≤350 cells per μL]) and received a 5 μg dose of glycoconjugate GBS vaccine (serotypes Ia, Ib, and III, with CRM197 [Novartis Vaccines, Siena, Italy]) intramuscularly at 24–35 weeks' gestation. GBS serotype-specific antibody concentrations were measured before vaccination (day 1), day 15, day 31, and at delivery, and in infants at birth and day 42 of life. The primary outcomes were safety in mothers and infants and the amount of placental transfer of GBS serotype-specific antibodies from mothers to their infants. All immunogenicity and safety analyses were done on the full analysis set, including participants who, or whose mother, correctly received the vaccine and who provided at least one valid assessable serum sample. This study is registered with ClinicalTrials.gov, number NCT01412801.Findings270 women and 266 infants were enrolled between Sept 26, 2011, and Dec 4, 2012 (90 women and 87 infants without HIV, 89 and 88 with HIV and high CD4 cell counts, and 91 and 91 with HIV and low CD4 cell counts, respectively). Seven women were lost to follow-up, six withdrew consent, one died, and two relocated. Eight infants died or were stillborn and two were lost to follow-up. Across serotypes, fold change in antibody concentrations were higher for the HIV-uninfected group than the HIV-infected groups. Transfer ratios were similar across all three groups (0·49–0·72; transfer ratio is infant geometric mean antibody concentration in blood collected within 72 h of birth divided by maternal geometric mean antibody concentration in blood collected at delivery); however, at birth, maternally derived serotype-specific antibody concentrations were lower for infants born to women infected with HIV (0·52–1·62 μg/mL) than for those born to women not infected with HIV (2·67–3·91 μg/mL). 151 (57%) of 265 women reported at least one solicited adverse reaction: 39 (45%) of 87 women with HIV and low CD4 cell counts, 52 (59%) of 88 women with HIV and high CD4 cell counts, and 60 (67%) of 90 women in the HIV-uninfected group. 49 (18%) of 269 women had at least one adverse event deemed possibly related to the vaccine (six [7%] in the HIV and low CD4 cell count group, 12 [13%] in the HIV and high CD4 cell count group, and 21 [23%] in the HIV-uninfected group), as did three (1%) of 266 neonates (zero, two [1%], and one [1%]); none of these events was regarded as seriou...

The respiratory syncytial virus (RSV) is a serious pediatric pathogen for which there is currently no clinically-approved vaccine. This report describes the design and testing of a new RSV vaccine construct (rSV-RSV-F), created by the recombination of an RSV F sequence with the murine parainfluenza virus type 1 (Sendai virus, SV) genome. SV was selected as the vaccine backbone for this study, because it has previously been shown to elicit high-magnitude, durable immune activities in animal studies and has advanced to human safety trials as a xenogenic vaccine for human parainfluenza virus-type 1 (hPIV-1). Cells infected with the recombinant SV expressed RSV F protein, but F was not incorporated into progeny SV virions. When cotton rats were inoculated with the vaccine, high-titer RSV-binding and neutralizing antibodies were induced as well as interferon-γ-producing T-cells. Most striking was the protection against intra-nasal RSV challenge conferred by the vaccine. The rSV-RSV-F construct was also tested as a mixture with a second SV construct expressing the RSV G protein, but no clear advantage was demonstrated by combining the two vaccines. As a final analysis, the efficacy of the rSV-RSV-F vaccine was tested against an array of RSV isolates. Results showed that neutralizing and protective responses were effective against RSV isolates of both A and B subtypes. Together, experimental results encourage promotion of this recombinant SV construct as a vaccine candidate for the prevention of RSV in humans.

ClinicalTrials.gov, www.clinicaltrials.gov, NCT01446289.