Shortening HIV vaccine regimens to achieve high coverage.
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ABSTRACT:
SUBMITTER: Blasi M
PROVIDER: S-EPMC7276282 | biostudies-literature | 2020 Jun
REPOSITORIES: biostudies-literature
Publications
Shortening HIV vaccine regimens to achieve high coverage.
Blasi Maria M Fouda Genevieve G GG
The lancet. HIV 20200217 6
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Project description:In the past 2 years, remarkable advances have been made in shortening tuberculosis (TB) treatment. In particular, four clinical trials (Study 31/A5349, Nix-TB, ZeNix and TB-PRACTECAL) have provided evidence of the efficacy of regimens based on new and repurposed drugs: the 4-month regimen for drug-susceptible TB, and the 6-month bedaquiline-pretomanid-linezolid regimen with or without moxifloxacin for multidrug-resistant/rifampicin-resistant TB. Even if the evidence at the basis of these new regimens is compelling, several questions remain open, particularly concerning linezolid dose finding, the upsurging threat of bedaquiline-resistant Mycobacterium tuberculosis and the feasibility of applying these results to the paediatric population. Several ongoing trials may fill the remaining gaps and produce further reliable evidence to address the outstanding questions in TB treatment shortening.
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Project description:In the past 2 years, remarkable advances have been made in shortening tuberculosis (TB) treatment. In particular, four clinical trials (Study 31/A5349, Nix-TB, ZeNix and TB-PRACTECAL) have provided evidence of the efficacy of regimens based on new and repurposed drugs: the 4-month regimen for drug-susceptible TB, and the 6-month bedaquiline-pretomanid-linezolid regimen with or without moxifloxacin for multidrug-resistant/rifampicin-resistant TB. Even if the evidence at the basis of these new regimens is compelling, several questions remain open, particularly concerning linezolid dose finding, the upsurging threat of bedaquiline-resistant Mycobacterium tuberculosis and the feasibility of applying these results to the paediatric population. Several ongoing trials may fill the remaining gaps and produce further reliable evidence to address the outstanding questions in TB treatment shortening.
| S-EPMC10567072 | biostudies-literature
Project description:In the RV144 trial, vaccine-induced V1V2 IgG correlated with decreased HIV-1 risk. We investigated circulating antibody specificities in two phase 1 poxvirus prime-protein boost clinical trials conducted in South Africa: HVTN 097 (subtype B/E) and HVTN 100 (subtype C). With cross-subtype peptide microarrays and multiplex binding assays, we probed the magnitude and breadth of circulating antibody responses to linear variable loop 2 (V2) and conformational V1V2 specificities. Antibodies targeting the linear V2 epitope, a correlate of decreased HIV-1 risk in RV144, were elicited up to 100% and 61% in HVTN 097 and HVTN 100, respectively. Despite higher magnitude of envelope-specific responses in HVTN 100 compared to HVTN 097 (p's < 0.001), the magnitude and positivity for V2 linear epitope and V1V2 proteins were significantly lower in HVTN 100 compared to HVTN 097. Meanwhile, responses to other major linear epitopes including the variable 3 (V3) and constant 5 (C5) epitopes were higher in HVTN 100 compared to HVTN 097. Our data reveal substantial differences in the circulating antibody specificities induced by vaccination in these two canarypox prime-protein boost trials. Our findings suggest that the choice of viral sequences in prime-boost vaccine regimens, and potentially adjuvants and immunogen dose, influence the elicitation of V2-specific antibodies.
| S-EPMC7005751 | biostudies-literature
Project description:An effective human immunodeficiency virus type 1 (HIV-1) vaccine is the best solution for halting the acquired immune deficiency syndrome epidemic. Here, we describe the design and preclinical immunogenicity of T-cell vaccine expressing novel immunogens tHIVconsvX, vectored by DNA, simian (chimpanzee) adenovirus, and poxvirus modified vaccinia virus Ankara (MVA), a combination highly immunogenic in humans. The tHIVconsvX immunogens combine the three leading strategies for elicitation of effective CD8(+) T cells: use of regions of HIV-1 proteins functionally conserved across all M group viruses (to make HIV-1 escape costly on viral fitness), inclusion of bivalent complementary mosaic immunogens (to maximize global epitope matching and breadth of responses, and block common escape paths), and inclusion of epitopes known to be associated with low viral load in infected untreated people (to induce field-proven protective responses). tHIVconsvX was highly immunogenic in two strains of mice. Furthermore, the magnitude and breadth of CD8(+) T-cell responses to tHIVconsvX-derived peptides in treatment-naive HIV-1(+) patients significantly correlated with high CD4(+) T-cell count and low viral load. Overall, the tHIVconsvX design, combining the mosaic and conserved-region approaches, provides an indisputably better coverage of global HIV-1 variants than previous T-cell vaccines. These immunogens delivered in a highly immunogenic framework of adenovirus prime and MVA boost are ready for clinical development.
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Project description:BackgroundThe identification of baseline host determinants that associate with robust HIV-1 vaccine-induced immune responses could aid HIV-1 vaccine development. We aimed to assess both the collective and relative performance of baseline characteristics in classifying individual participants in nine different Phase 1-2 HIV-1 vaccine clinical trials (26 vaccine regimens, conducted in Africa and in the Americas) as High HIV-1 vaccine responders.MethodsThis was a meta-analysis of individual participant data, with studies chosen based on participant-level (vs. study-level summary) data availability within the HIV-1 Vaccine Trials Network. We assessed the performance of 25 baseline characteristics (demographics, safety haematological measurements, vital signs, assay background measurements) and estimated the relative importance of each characteristic in classifying 831 participants as High (defined as within the top 25th percentile among positive responders or above the assay upper limit of quantification) versus Non-High responders. Immune response outcomes included HIV-1-specific serum IgG binding antibodies and Env-specific CD4+ T-cell responses assessed two weeks post-last dose, all measured at central HVTN laboratories. Three variable importance approaches based on SuperLearner ensemble machine learning were considered.FindingsOverall, 30.1%, 50.5%, 36.2%, and 13.9% of participants were categorized as High responders for gp120 IgG, gp140 IgG, gp41 IgG, and Env-specific CD4+ T-cell vaccine-induced responses, respectively. When including all baseline characteristics, moderate performance was achieved for the classification of High responder status for the binding antibody responses, with cross-validated areas under the ROC curve (CV-AUC) of 0.72 (95% CI: 0.68, 0.76) for gp120 IgG, 0.73 (0.69, 0.76) for gp140 IgG, and 0.67 (95% CI: 0.63, 0.72) for gp41 IgG. In contrast, the collection of all baseline characteristics yielded little improvement over chance for predicting High Env-specific CD4+ T-cell responses [CV-AUC: 0.53 (0.48, 0.58)]. While estimated variable importance patterns differed across the three approaches, female sex assigned at birth, lower height, and higher total white blood cell count emerged as significant predictors of High responder status across multiple immune response outcomes using Approach 1. Of these three baseline variables, total white blood cell count ranked highly across all three approaches for predicting vaccine-induced gp41 and gp140 High responder status.InterpretationThe identified features should be studied further in pursuit of intervention strategies to improve vaccine responses and may be adjusted for in analyses of immune response data to enhance statistical power.FundingNational Institute of Allergy and Infectious Diseases (UM1AI068635 to YH, UM1AI068614 to GDT, UM1AI068618 to MJM, and UM1 AI069511 to MCK), the Duke CFAR P30 AI064518 to GDT, and National Institute of Dental and Craniofacial Research (R01DE027245 to JJK). This work was also supported by the Bill and Melinda Gates Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of any of the funding sources.
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Project description:BackgroundThe Advisory Committee on Immunization Practice of Thailand prioritizes seasonal influenza vaccinations for populations who are at highest risk for serious complications (pregnant women, children 6 months-2 years, persons ≥65 years, persons with chronic diseases, obese persons), and healthcare personnel and poultry cullers. The Thailand government purchases seasonal influenza vaccine for these groups. We assessed vaccination coverage among high-risk groups in Thailand from 2010 to 2012.MethodsNational records on persons who received publicly purchased vaccines from 2010 to 2012 were analyzed by high-risk category. Denominator data from multiple sources were compared to calculate coverage. Vaccine coverage was defined as the proportion of individuals in each category who received the vaccine. Vaccine wastage was defined as the proportion of publicly purchased vaccines that were not used.ResultsFrom 2010 to 2012, 8.18 million influenza vaccines were publicly purchased (range, 2.37-3.29 million doses/year), and vaccine purchases increased 39% over these years. Vaccine wastage was 9.5%. Approximately 5.7 million (77%) vaccine doses were administered to persons ≥65 years and persons with chronic diseases, 1.4 million (19%) to healthcare personnel/poultry cullers, 82,570 (1.1%) to children 6 months-2 years, 78,885 (1.1%) to obese persons, 26,481 (0.4%) to mentally disabled persons, and 17,787 (0.2%) to pregnant women. Between 2010 and 2012, coverage increased among persons with chronic diseases (8.6% versus 14%; p<0.01) and persons ≥65 years (12%, versus 20%; p<0.01); however, coverage decreased for mentally disabled persons (6.1% versus 4.9%; p<0.01), children 6 months-2 years (2.3% versus 0.9%; p<0.01), pregnant women (1.1% versus 0.9%; p<0.01), and obese persons (0.2% versus 0.1%; p<0.01).ConclusionsFrom 2010 to 2012, the availability of publicly purchased vaccines increased. While coverage remained low for all target groups, coverage was highest among persons ≥65 years and persons with chronic diseases. Annual coverage assessments are necessary to promote higher coverage among high-risk groups in Thailand.
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