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Background: Adjuvants are widely used to enhance and/or direct vaccine-induced immune responses yet rarely evaluated head-to-head. Our trial directly compared immune responses elicited by MF59 versus alum adjuvants in the RV144-like HIV vaccine regimen modified for the Southern African region. The RV144 trial of a recombinant canarypox vaccine vector expressing HIV env subtype B (ALVAC-HIV) prime followed by ALVAC-HIV plus a bivalent gp120 protein vaccine boost adjuvanted with alum is the only trial to have shown modest HIV vaccine efficacy. Data generated after RV144 suggested that use of MF59 adjuvant might allow lower protein doses to be used while maintaining robust immune responses. We evaluated safety and immunogenicity of an HIV recombinant canarypox vaccine vector expressing HIV env subtype C (ALVAC-HIV) prime followed by ALVAC-HIV plus a bivalent gp120 protein vaccine boost (gp120) adjuvanted with alum (ALVAC-HIV+gp120/alum) or MF59 (ALVAC-HIV+gp120/MF59) or unadjuvanted (ALVAC-HIV+gp120/no-adjuvant) and a regimen where ALVAC-HIV+gp120 adjuvanted with MF59 was used for the prime and boost (ALVAC-HIV+gp120/MF59 coadministration). Methods and findings: Between June 19, 2017 and June 14, 2018, 132 healthy adults without HIV in South Africa, Zimbabwe, and Mozambique were randomized to receive intramuscularly: (1) 2 priming doses of ALVAC-HIV (months 0 and 1) followed by 3 booster doses of ALVAC-HIV+gp120/MF59 (months 3, 6, and 12), n = 36; (2) 2 priming doses of ALVAC-HIV (months 0 and 1) followed by 3 booster doses of ALVAC-HIV+gp120/alum (months 3, 6, and 12), n = 36; (3) 4 doses of ALVAC-HIV+gp120/MF59 coadministered (months 0, 1, 6, and 12), n = 36; or (4) 2 priming doses of ALVAC-HIV (months 0 and 1) followed by 3 booster doses of ALVAC-HIV+gp120/no adjuvant (months 3, 6, and 12), n = 24. Primary outcomes were safety and occurrence and mean fluorescence intensity (MFI) of vaccine-induced gp120-specific IgG and IgA binding antibodies at month 6.5. All vaccinations were safe and well-tolerated; increased alanine aminotransferase was the most frequent related adverse event, occurring in 2 (1.5%) participants (1 severe, 1 mild). At month 6.5, vaccine-specific gp120 IgG binding antibodies were detected in 100% of vaccinees for all 4 vaccine groups. No significant differences were seen in the occurrence and net MFI of vaccine-specific IgA responses between the ALVAC-HIV+gp120/MF59-prime-boost and ALVAC-HIV+gp120/alum-prime-boost groups or between the ALVAC-HIV+gp120/MF59-prime-boost and ALVAC-HIV+gp120/MF59 coadministration groups. Limitations were the relatively small sample size per group and lack of evaluation of higher gp120 doses. Conclusions: Although MF59 was expected to enhance immune responses, alum induced similar responses to MF59, suggesting that the choice between these adjuvants may not be critical for the ALVAC+gp120 regimen. Trial registration: HVTN 107 was registered with the South African National Clinical Trials Registry (DOH-27-0715-4894) and ClinicalTrials.gov (NCT03284710). Zoe Moodie and colleagues investigate the safety and immunogenicity of a subtype C ALVAC-HIV vaccine prime plus bivalent subtype C gp120 vaccine boost adjuvanted with MF59 or alum in healthy adults without HIV. Author summary: Why was this study done?: Vaccines may use an adjuvant to help the body produce a stronger immune response. Results from animal studies suggested that the MF59 adjuvant generates better immunogenicity than the alum adjuvant when given as part of an HIV vaccine and could also allow a lower dose of protein to be used. Our clinical trial was done to directly assess in humans whether MF59 leads to better immune responses than alum when given with protein in a subtype C canarypox vaccine (ALVAC-HIV) prime followed by ALVAC-HIV plus a bivalent gp120 protein vaccine boost (gp120). What did the researchers do and find?: Vaccines were safe and well-tolerated over the 18 months of follow-up. 100% of vaccinees had vaccine-specific gp120 IgG binding antibodies at month 6.5. Immune responses for the ALVAC-HIV+gp120/MF59 group and the ALVAC-HIV+gp120/alum group were similar. What do these findings mean?: Contrary to expectation, the choice between MF59 and alum does not seem critical to the immune responses assessed in the peripheral blood for this subtype C ALVAC-HIV+gp120 prime-boost regimen. The main limitations of our study were the small vaccine group sample sizes and that higher doses of gp120 protein were not evaluated. [ABSTRACT FROM AUTHOR]

Background: Natural immunity against Mycobacterium tuberculosis exists, and > 90% of those infected remain disease-free. Innate and adaptive immune responses required to mediate such protection against tuberculosis (TB) are, however, poorly understood.Methods: This is an analytical study exploring protective and non-protective pathways of immunity against Mycobacterium tuberculosis. Adults without HIV infection are recruited at community healthcare clinics in high TB incidence areas of the Western Cape Province, South Africa. Data regarding participants' medical, social and medication usage will be collected, and clinical examinations and point-of-care tests documented. Reference tests for TB (chest radiographs and sputum tests for GeneXpert MTB/RIF Ultra®, Auramine smear and liquid cultures) and investigations to classify infection states [interferon-gamma release assay (IGRA) and SARS-CoV-2 polymerase chain reaction (PCR) nasopharyngeal swab and IgG], are done on all participants who meet the inclusion criteria. 18F-Fluorodeoxyglucose positron emission tomography combined with computerized tomography will be done on all close contacts (contacts) and healthy control (controls) participants. Participants are divided into 12 study groups representing a spectrum of TB clinical phenotypes and prior SARS-CoV-2 infection based on their TB status, exposure history, results of IGRA test at baseline and 3 months, SARS-CoV-2 serology, and PCR results, and for contacts and controls, PET-CT imaging findings indicative of sub-clinical TB lesions. Samples for experimental assays include whole blood for isolation of peripheral blood mononuclear cells and blood in PAXgene® tubes for RNA isolation. All SARS-CoV-2 PCR negative study participants undergo bronchoscopy for collecting bronchoalveolar lavage samples.Discussion: The paired blood and BAL samples will be used for comprehensive analyses of the tissue-specific and systemic immunity that will include e.g., cytometry by time-of-flight analyses, RNA-sequencing, multiplex immunoassays, epigenetic analysis, and mechanistic studies of control of infection by Mycobacterium tuberculosis. Results will be integrated with those from mice and non-human primate studies to provide a comprehensive analysis of protective pathways in natural and vaccine-induced immunity against Mycobacterium tuberculosis. [ABSTRACT FROM AUTHOR]

Summary: Significant progress has been made in advancing the development pipeline for a new and more effective TB vaccine with some candidate vaccines now in late stage clinical evaluation. However, progress has been hampered by an incomplete understanding of the components of a protective immune response and limited animal models, rendering the field unable to reliably predict vaccine efficacy earlier in preclinical development, including by evaluation in animal models, and limiting the predictive utility of comparing immunogenic effects across vaccine candidates in phase I/II studies. Consequently, new candidate vaccines have to be evaluated for efficacy in large-scale phase II/III trials using clinical endpoints. Apart from the technical challenges of characterising TB incidence in target populations at high risk of acquiring TB disease and standardising case definitions in order to improve both the sensitivity and more importantly the specificity of trial endpoints, there is an urgency in expanding and supporting the considerable trial infrastructure that will be required to evaluate and ultimately license a new TB vaccine. In the longer term, implementation strategies are dependent on what policy makers most value. Economic analyses will be essential to guide policy and implementation. This paper outlines the gaps and challenges and identifies solutions for effectively developing and efficiently introducing a new TB vaccine. [ABSTRACT FROM AUTHOR]

Background: HVTN 100 evaluated the safety and immunogenicity of an HIV subtype C pox-protein vaccine regimen, investigating a 12-month booster to extend vaccine-induced immune responses.Methods and Findings: A phase 1-2 randomized double-blind placebo-controlled trial enrolled 252 participants (210 vaccine/42 placebo; median age 23 years; 43% female) between 9 February 2015 and 26 May 2015. Vaccine recipients received ALVAC-HIV (vCP2438) alone at months 0 and 1 and with bivalent subtype C gp120/MF59 at months 3, 6, and 12. Antibody (IgG, IgG3 binding, and neutralizing) and CD4+ T-cell (expressing interferon-gamma, interleukin-2, and CD40 ligand) responses were evaluated at month 6.5 for all participants and at months 12, 12.5, and 18 for a randomly selected subset. The primary analysis compared IgG binding antibody (bAb) responses and CD4+ T-cell responses to 3 vaccine-matched antigens at peak (month 6.5 versus 12.5) and durability (month 12 versus 18) timepoints; IgG responses to CaseA2_gp70_V1V2.B, a primary correlate of risk in RV144, were also compared at these same timepoints. Secondary and exploratory analyses compared IgG3 bAb responses, IgG bAb breadth scores, neutralizing antibody (nAb) responses, antibody-dependent cellular phagocytosis, CD4+ polyfunctionality responses, and CD4+ memory sub-population responses at the same timepoints. Vaccines were generally safe and well tolerated. During the study, there were 2 deaths (both in the vaccine group and both unrelated to study products). Ten participants became HIV-infected during the trial, 7% (3/42) of placebo recipients and 3% (7/210) of vaccine recipients. All 8 serious adverse events were unrelated to study products. Less waning of immune responses was seen after the fifth vaccination than after the fourth, with higher antibody and cellular response rates at month 18 than at month 12: IgG bAb response rates to 1086.C V1V2, 21.0% versus 9.7% (difference = 11.3%, 95% CI = 0.6%-22.0%, P = 0.039), and ZM96.C V1V2, 21.0% versus 6.5% (difference = 14.5%, 95% CI = 4.1%-24.9%, P = 0.004). IgG bAb response rates to all 4 primary V1V2 antigens were higher 2 weeks after the fifth vaccination than 2 weeks after the fourth vaccination: 87.7% versus 75.4% (difference = 12.3%, 95% CI = 1.7%-22.9%, P = 0.022) for 1086.C V1V2, 86.0% versus 63.2% (difference = 22.8%, 95% CI = 9.1%-36.5%, P = 0.001) for TV1c8.2.C V1V2, 67.7% versus 44.6% (difference = 23.1%, 95% CI = 10.4%-35.7%, P < 0.001) for ZM96.C V1V2, and 81.5% versus 60.0% (difference = 21.5%, 95% CI = 7.6%-35.5%, P = 0.002) for CaseA2_gp70_V1V2.B. IgG bAb response rates to the 3 primary vaccine-matched gp120 antigens were all above 90% at both peak timepoints, with no significant differences seen, except a higher response rate to ZM96.C gp120 at month 18 versus month 12: 64.5% versus 1.6% (difference = 62.9%, 95% CI = 49.3%-76.5%, P < 0.001). CD4+ T-cell response rates were higher at month 18 than month 12 for all 3 primary vaccine-matched antigens: 47.3% versus 29.1% (difference = 18.2%, 95% CI = 2.9%-33.4%, P = 0.021) for 1086.C, 61.8% versus 38.2% (difference = 23.6%, 95% CI = 9.5%-37.8%, P = 0.001) for TV1.C, and 63.6% versus 41.8% (difference = 21.8%, 95% CI = 5.1%-38.5%, P = 0.007) for ZM96.C, with no significant differences seen at the peak timepoints. Limitations were that higher doses of gp120 were not evaluated, this study was not designed to investigate HIV prevention efficacy, and the clinical significance of the observed immunological effects is uncertain.Conclusions: In this study, a 12-month booster of subtype C pox-protein vaccines restored immune responses, and slowed response decay compared to the 6-month vaccination.Trial Registration: ClinicalTrials.gov NCT02404311. South African National Clinical Trials Registry (SANCTR number: DOH--27-0215-4796). [ABSTRACT FROM AUTHOR]

Background: Although livestock vaccination is effective in preventing Rift Valley fever (RVF) epidemics, there are concerns about safety and effectiveness of the only commercially available RVF Smithburn vaccine. We conducted a randomized controlled field trial to evaluate the immunogenicity and safety of the new RVF Clone 13 vaccine, recently registered in South Africa. Methods: In a blinded randomized controlled field trial, 404 animals (85 cattle, 168 sheep, and 151 goats) in three farms in Kenya were divided into three groups. Group A included males and non-pregnant females that were randomized and assigned to two groups; one vaccinated with RVF Clone 13 and the other given placebo. Groups B included animals in 1st half of pregnancy, and group C animals in 2nd half of pregnancy, which were also randomized and either vaccinated and given placebo. Animals were monitored for one year and virus antibodies titers assessed on days 14, 28, 56, 183 and 365. Results: In vaccinated goats (N = 72), 72% developed anti-RVF virus IgM antibodies and 97% neutralizing IgG antibodies. In vaccinated sheep (N = 77), 84% developed IgM and 91% neutralizing IgG antibodies. Vaccinated cattle (N = 42) did not develop IgM antibodies but 67% developed neutralizing IgG antibodies. At day 14 post-vaccination, the odds of being seropositive for IgG in the vaccine group was 3.6 (95% CI, 1.5 – 9.2) in cattle, 90.0 (95% CI, 25.1 – 579.2) in goats, and 40.0 (95% CI, 16.5 – 110.5) in sheep. Abortion was observed in one vaccinated goat but histopathologic analysis did not indicate RVF virus infection. There was no evidence of teratogenicity in vaccinated or placebo animals. Conclusions: The results suggest RVF Clone 13 vaccine is safe to use and has high (>90%) immunogenicity in sheep and goats but moderate (> 65%) immunogenicity in cattle. Author Summary: Although livestock vaccination is effective in preventing Rift Valley fever (RVF) outbreaks, there are concerns about safety and effectiveness of the only commercially available vaccine for the disease. Here, we conducted a field trial in Kenya to evaluate the safety and ability to induce protection for a new RVF vaccine, referred to as Clone 13, that was recently registered in South Africa. A total of 404 animals, consisting of cattle, sheep, and goats, were divided two groups and one group was vaccinated with Clone 13 vaccine while the other group was not vaccinated. The animals were followed for one year and analyzed for RVF antibody levels at days 14, 28, 56, 183, and 365 after vaccination. Between 91% and 97% of vaccinated sheep and goats develop antibodies to the vaccine, whereas only 67% of the vaccinated cattle developed antibodies. These finding indicate that the Clone 13 vaccine induces high levels of protective antibodies in sheep and goats and moderate levels in cattle. The vaccine was safe since none of vaccinated animals developed evidence of RVF disease including deformities in newborns, and only 1 out of 120 pregnant animals had an abortion that was not associated with the RVF disease. [ABSTRACT FROM AUTHOR]

The highly pathogenic avian influenza virus H5N1 is a potent pandemic threat because of its frequent transmission from birds to humans and the increasing possibility of human to human transmission. During the 2009 H1N1 pandemic it was clear that rapid influenza vaccine production is a problem worldwide. Additionally, developing countries like South Africa generally cannot produce their own influenza vaccines because the traditional egg-based vaccine production method currently employed is too lengthy and too difficult to establish. As part of an exercise aimed at exploring the feasibility of producing emergency response influenza vaccines, we investigated an experimental DNA vaccine to the H5N1 influenza virus. We focused on the virion haemagglutinin, because it elicits the primary neutralising immune response following infection. Accordingly, we developed an H5N1 DNA vaccine with full-length and truncated versions of the haemagglutinin gene, to match previously developed protein candidates. Vaccinated mice developed a strong antibody response to the haemagglutinin protein. In addition, the full-length H5 gene elicited high haemagglutination inhibition titres in mice, indicating that it has potential as a candidate pandemic vaccine for South Africa. [ABSTRACT FROM AUTHOR]

Factors predicting suboptimal CD4 cell recovery have been studied in HIV clade-B infected US and European populations. It is, however, uncertain to what extent these results are applicable to HIV clade-C infected African populations. Multivariate analysis using logistic regression and longitudinal analyses using mixed models were employed to assess the impact of age, gender, baseline CD4 cell count, hemoglobin, body mass index (BMI), tuberculosis and other opportunistic co-infections, and frequencies of regimen change on CD4 cell recovery at 12 and 30 months and on overtime change in CD4 cells among 442 virologically suppressed South Africans. Despite adequate virological response 37% (95% CI:32%-42%) and 83% (95% CI:79%-86%) of patients on antiretroviral therapy failed to restore CD4 cell counts $200 cells/mm3 after 12 and ≥500 cells/ mm3 after 30 months, respectively, in this South African cohort. Critical risk factors for inadequate recovery were older age (p = 0.001) and nadir CD4 cell count at ART initiation (p<0.0001), while concurrent TB co-infection, BMI, baseline hemoglobin, gender and antiretroviral regimen were not significant risk factors. These data suggest that greater efforts are needed to identify and treat HAART-eligible patients prior to severe CD4 cell decline or achievement of advanced age. [ABSTRACT FROM AUTHOR]

The article discusses a study which examined the influence of different helminth infection phenotypes on immune responses against Human Immunodeficiency Virus (HIV) in co-infected adults in South Africa. The study used both coproscopy and Ascaris lumbricoides-specific serum IgE to distinguish between different helminth infection phenotypes and their effects on immune responses in HIV co-infected individuals.

Background: The failure of specific types of human papillomaviruses (HPV) to raise effective immune responses may be important in the pathogenesis of cervical cancer, the second most common cancer in South African women. Polymorphisms of a number of cytokine genes have been implicated in inducing susceptibility or resistance to cancers caused by infectious agents owing to their role in determining host immune response. Polymorphisms of IL-10 and IFN-γ genes are believed to influence the expression and/or secretion levels of their respective cytokines. Methods and Results: In this study, women with histologically proven cancer of the cervix (n = 458) and hospital-based controls (n = 587) were investigated for bi-allelic -1082 (A/G) polymorphisms of IL-10 and the biallelic +874(A/T) polymorphisms of IFN-γ. In addition, the distributions of the allelic frequencies were stratified in both the African and mixed race population groups of South Africa. We found striking differences in the allele distribution of IFN-γ (X2 = 0.02) among the two ethnic groups. A significant increase in the allele distribution of the IFN-γ AA genotype was found in the African group compared to the mixed population group (OR, 0.5; 95% CI, 0.2-1.0). For IL-10 there were no significant allelic differences between the two South African ethnic groups. Furthermore, when the ethnic groups were combined the IL-10 allelic frequencies in the combined South African data were similar to those observed in an Oriental population from Southern China and in an Italian population. However, the allele frequencies of the IFN-γ genotype among the two South African ethnic groups were different when compared to an Italian Caucasoid group. While crude analysis of these data showed both statistically significantly increased and diminished risks of cervical cancer among high producers of INF-γ and low producers of IL-10 respectively, these associations were no longer significant when the data were adjusted for confounding factors. Conclusion: These findings demonstrate a clear correlation between ethnicity and IFN-γ polymorphism across different population groups. However, these differences in ethnicity and gene polymorphisms in the aforementioned cytokines are suggested not to influence the development of invasive cervical cancer but may represent an important susceptibility biomarker for other diseases and should be explored further. [ABSTRACT FROM AUTHOR]

Purpose of the review: This review highlights the role of angiogenesis, lymphangiogenesis, and immune markers in human immunodeficiency virus (HIV)-associated preeclamptic (PE) pregnancies in an attempt to unravel the mysteries underlying the duality of both conditions in South Africa. Recent findings: Studies demonstrate that HIV-infected pregnant women develop PE at a lower frequency than uninfected women. In contrast, women receiving highly active anti-retroviral therapy (HAART) are more inclined to develop PE, stemming from an imbalance of angiogenesis, lymphangiogenesis, and immune response. Summary: In view of the paradoxical effect of HIV infection on PE development, this study examines angiogenesis, lymphangiogenesis, and immune markers in the highly HIV endemic area of KwaZulu-Natal. We believe that HAART re-constitutes the immune response in PE, thereby predisposing women to PE development. This susceptibility is due to an imbalance in the angiogenic/lymphangiogenic/immune response as compared to normotensive pregnant women. Further large-scale studies are urgently required to investigate the effect of the duration of HAART on PE development. [ABSTRACT FROM AUTHOR]