Group B streptococcus vaccination in pregnant women with or without HIV in Africa: a non-randomised phase 2, open-label, multicentre trial

Background Neonates 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. Methods In 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 mu L], and infection and low CD4 cell count [>50 to <= 350 cells per mu L]) and received a 5 mu g 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. Findings 270 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 mu g/mL) than for those born to women not infected with HIV (2.67-3.91 mu g/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 serious. Interpretation The vaccine was less immunogenic in women infected with HIV than it was in those not infected, irrespective of CD4 cell count, resulting in lower levels of serotype-specific maternal antibody transferred to infants, which could reduce vaccine protection against invasive GBS disease. A validated assay and correlate of protection is needed to understand the potential protective value of this vaccine. Copyright (C) Heyderman et al. Open Access article distributed under the terms of CC BY

Clade, Country and Region-specific HIV-1 Vaccines: Are they necessary?

Today, scientists are often encouraged to custom-design vaccines based on a particular country or clade. Here, we review the scientific literature and then suggest that the overwhelming endeavor to produce a unique vaccine for every world region or virus subtype may not be necessary

Heterologous Prime-Boost HIV-1 Vaccination Regimens in Pre-Clinical and Clinical Trials

Currently, there are more than 30 million people infected with HIV-1 and thousands more are infected each day. Vaccination is the single most effective mechanism for prevention of viral disease, and after more than 25 years of research, one vaccine has shown somewhat encouraging results in an advanced clinical efficacy trial. A modified intent-to-treat analysis of trial results showed that infection was approximately 30% lower in the vaccine group compared to the placebo group. The vaccine was administered using a heterologous prime-boost regimen in which both target antigens and delivery vehicles were changed during the course of inoculations. Here we examine the complexity of heterologous prime-boost immunizations. We show that the use of different delivery vehicles in prime and boost inoculations can help to avert the inhibitory effects caused by vector-specific immune responses. We also show that the introduction of new antigens into boost inoculations can be advantageous, demonstrating that the effect of ‘original antigenic sin’ is not absolute. Pre-clinical and clinical studies are reviewed, including our own work with a three-vector vaccination regimen using recombinant DNA, virus (Sendai virus or vaccinia virus) and protein. Promising preliminary results suggest that the heterologous prime-boost strategy may possibly provide a foundation for the future prevention of HIV-1 infections in humans

Reversal of malignant cell growth phenotype by hydroxyurea-induced loss of Epstein-BARR virus episomes: 146

Background: Little consideration has been given to virus-directed therapy of EBV-associated AIDS malignancies, first, because latent herpesviruses are intractable to available antiviral chemotherapy and, second, because of the uncertainty that EBV makes any contribution to the long-term maintenance of the malignant cell phenotype. Using cell lines that reflects the phenotypic heterogeneity of AIDS-related lymphomas, we examined the effect of the ribonucleotide reductase inhibitor hydroxyurea (HU), known to accelerate loss of extrachromosomal DNA, on EBV episomal copy number and subsequent cell proliferation.Methods: EBV-positive lymphoblastoid cell lines (LCL) and Burkitt lymphoma (BL) cells were treated with low concentrations (50µM) of HU. EBV DNA content in treated versus untreated cells was measured serially by Southern blot and fluorescent in situ hybridization (FISH). Single cell clones from HU-treated BL cells, obtained via the cell sorter, were examined for growth characteristics in tumorigenicity assays.Results: Primary B cells immortalized by EBV (LCL) ceased to proliferate in HU and could not be maintained as long-term cultures. On FISH analysis of treated LCLs, individual cells were detected that did not contain hybridization signals implying complete climination of EBV episomes. The median episome count in HU-treated versus untreated LCLs was 6 versus 21(p\u3c0.0001, Wilcoxon 2-sample test). A control LCL, IB4, which contains only integrated (not episomal) EBV DNA, was not growth inhibited in the presence of HU, implicating episomal loss and not drug toxicity in the altered growth phenotype. In the case of the BL cell line Akata, there was a 99.5% reduction of EBV DNA by Southern blot analysis after 15 cell population doublings on HU. By contrast, there was no EBV DNA loss from untreated controls. At an individual cell level, approximately half the treated cells were EBV-negative by FISH. Of 131 single cell clones obtained from the treated population, 57 were EBV-negative. Unlike EBV-positive counterparts, Akata clones cured of EBV episomes were no longer able to grow in 0.1% serum, form colonies in soft agar or produce tumors in SCID mice despite retaining the characteristic (8,14) rearrangement.Conclusion: These findings provide the first evidence for successful eradication of a latent herpesvirus from any cell population. They challenge the view that EBV is important only in the initiation of tumorigenesis, but plays no role in the long-term maintenance of the malignant cell phenotype. Together with the apparent reversal of EBV immortalization observed in primary B cells, these data suggest latent EBV is an appropriate and accessible therapeutic target and have prompted initiation of clinical trials of HU in EBV-related lymphoproliferative diseases of AIDS

Clustering of Th cell epitopes on exposed regions of HIV envelope despite defects in antibody activity

A long-standing question in the field of immunology concerns the factors that contribute to Th cell epitope immunodominance. For a number of viral membrane proteins, Th cell epitopes are localized to exposed protein surfaces, often overlapping with Ab binding sites. It has therefore been proposed that Abs on B cell surfaces selectively bind and protect exposed protein fragments during Ag processing, and that this interaction helps to shape the Th cell repertoire. While attractive in concept, this hypothesis has not been thoroughly tested. To test this hypothesis, we have compared Th cell peptide immunodominance in normal C57BL/6 mice with that in C57BL/6MT/MT mice (lacking normal B cell activity). Animals were first vaccinated with DNA constructs expressing one of three different HIV envelope proteins, after which the CD4 T cell response profiles were characterized toward overlapping peptides using an IFN- ELISPOT assay. We found a striking similarity between the peptide response profiles in the two mouse strains. Profiles also matched those of previous experiments in which different envelope vaccination regimens were used. Our results clearly demonstrate that normal Ab activity is not required for the establishment or maintenance of Th peptide immunodominance in the HIV envelope response. To explain the clustering of Th cell epitopes, we propose that localization of peptide on exposed envelope surfaces facilitates proteolytic activity and preferential peptide shuttling through the Ag processing pathway.<br /

A Recombinant Sendai Virus Is Controlled by CD4+ Effector T Cells Responding to a Secreted Human Immunodeficiency Virus Type 1 Envelope Glycoprotein▿

The importance of antigen-specific CD4+ helper T cells in virus infections is well recognized, but their possible role as direct mediators of virus clearance is less well characterized. Here we describe a recombinant Sendai virus strategy for probing the effector role(s) of CD4+ T cells. Mice were vaccinated with DNA and vaccinia virus recombinant vectors encoding a secreted human immunodeficiency virus type 1 (HIV-1) envelope protein and then challenged with a Sendai virus carrying a homologous HIV-1 envelope gene. The primed mice showed (i) prompt homing of numerous envelope-primed CD4+ T cell populations to the virus-infected lung, (ii) substantial production of gamma interferon, and interleukin-2 (IL-2), IL-4, and IL-5 in that site, and (iii) significantly reduced pulmonary viral load. The challenge experiments were repeated with immunoglobulin−/− μMT mice in the presence or absence of CD8+ and/or CD4+ T cells. These selectively immunodeficient mice were protected by primed CD4+ T cells in the absence of antibody or CD8+ T cells. Together, these results highlight the role of CD4+ T cells as direct effectors in vivo and, because this protocol gives such a potent response, identify an outstanding experimental model for further dissecting CD4+ T-cell-mediated immunity in the lung

Recombinant Sendai Virus Expressing the G Glycoprotein of Respiratory Syncytial Virus (RSV) Elicits Immune Protection against RSV

Although RSV causes serious pediatric respiratory disease, an effective vaccine does not exist. To capture the strengths of a live virus vaccine, we have used the murine parainfluenza virus type 1 (Sendai virus [SV]) as a xenogeneic vector to deliver the G glycoprotein of RSV. It was previously shown (J. L. Hurwitz, K. F. Soike, M. Y. Sangster, A. Portner, R. E. Sealy, D. H. Dawson, and C. Coleclough, Vaccine 15:533-540, 1997) that intranasal SV protected African green monkeys from challenge with the related human parainfluenza virus type 1 (hPIV1), and SV has advanced to clinical trials as a vaccine for hPIV1 (K. S. Slobod, J. L. Shenep, J. Lujan-Zilbermann, K. Allison, B. Brown, R. A. Scroggs, A. Portner, C. Coleclough, and J. L. Hurwitz, Vaccine, in press). Recombinant SV expressing RSV G glycoprotein was prepared by using reverse genetics, and intranasal inoculation of cotton rats elicited RSV-specific antibody and elicited protection from RSV challenge. RSV G-recombinant SV is thus a promising live virus vaccine candidate for RSV