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Nikita Naicker,1 Hylton Rodel,2 Rubeshan Perumal,1 Yashica Ganga,2 Mallory Bernstein,2 Ntombi Benede,2 Salim Abdool Karim,1,3 Nesri Padayacthi,1,3 Alex Sigal,2,4,5 Kogieleum Naidoo1,3 1Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa; 2Africa Health Research Institute, Durban, South Africa; 3MRC-CAPRISA HIV-TB Pathogenesis and Treatment Research Unit, Doris Duke Medical Research Institute; University of KwaZulu-Natal, Durban, South Africa; 4School of Laboratory Medicine and Medical Sciences; University of KwaZulu-Natal, Durban, South Africa; 5Max Planck Institute for Infection Biology, Berlin, GermanyCorrespondence: Nikita Naicker, Doris Duke Medical Research Institute, 2nd Floor, 719 Umbilo Road, Durban, 4041, South Africa, Tel +27843011636, Email nikita.naicker@caprisa.orgIntroduction: Current TB treatment regimens are pathogen-directed and can be severely compromised by the development of drug resistance. Metformin has been proposed as an adjunctive therapy for TB, however relatively little is known about how metformin modulates the cellular interaction between Mtb and macrophages. We aimed to characterize how metformin modulates Mtb growth within macrophages.Methods: We utilized live cell tracking through time-lapse microscopy to better understand the biological effect of metformin in response to Mtb infection. Furthermore, the potent first-line anti-TB drug, isoniazid, was used as a comparator and as a companion drug.Results: Metformin caused a 14.2-fold decrease in Mtb growth compared to the untreated control. Metformin combined with isoniazid controlled Mtb growth is slightly better than isoniazid alone. Metformin demonstrated the ability to regulate the cytokine and chemokine response over a 72 hour period, better than isoniazid only.Conclusion: We provide novel evidence that metformin controls mycobacterial growth by increasing host cell viability, and a direct and independent pro-inflammatory response to Mtb. Understanding the impact of metformin on Mtb growth within macrophages will advance our current knowledge on metformin as an adjunctive therapy, providing a new host-directed approach to TB treatment.Keywords: metformin, tuberculosis, host-directed therapy, INH, adjunctive therapy

Background: Vaccine adjuvants are detected by the innate immune system and influence adaptive immune responses. The modestly efficacious RV144 Thai trial used alum to adjuvant the gp120 protein boost, whereas the non-efficacious HVTN 702 South African trial used MF59. Volunteers enrolled in HVTN 107 (NCT03284710) were administered these adjuvants with a subtype C pox-protein vaccine, affording a unique opportunity to contrast systemic innate immune responses and potentially inform the results of HVTN 702. Methods: Eighteen volunteers were enrolled per group. T1, T2 and T4 received 2 doses of ALVAC-HIV followed by 3 doses of ALVAC-HIV plus subtype C gp120 administered with MF59 (T1), alum (T2), or un-adjuvanted (T4). T3 received 4 doses of ALVAC-HIV with MF59-adjuvanted gp120. Innate immune responses were measured pre-vaccination and at days 1, 3 and 7 after the first (T3) or third (T1,T2, T4) vaccinations. Alterations in circulating leukocytes were assessed by CBC. Thirty-one serum immunomodulatory mediators were quantitated. Results: Neutrophil concentrations increased on day 1 in all groups (FDR-p's < 0.02) and monocyte concentrations increased in T2,T3 and T4 (FDR-p's < 0.12); lymphocyte concentrations significantly decreased at day 1 only in T1 (FDR-p = 0.03). Serum cytokines were also significantly altered post-vaccination in all groups (FDR-p's < 0.2). On Day 1, nine cytokines were induced in T1, including pro-inflammatory IFN-g, CXCL10, TNF-a, IL-6, as well as CCL4 and IL-2, with many factors remaining elevated at Day 3 and returning to baseline on Day 7. In contrast, only IL-2 and IL-6 were induced in T2 on Day 1 and twelve factors were repressed on Day 7 relative to pre-vaccination, including IFN-g and monocyte-chemotactic factors CCL8, CCL13, and CCL22. Responses in the MF59 groups differed when co-administered at the first vaccination (T3) relative to the third vaccination (T1) with 12 cytokines repressed on Day 1 in T3. Conclusions: Alum-adjuvanted protein administered in a prime/boost regimen including ALVAC-HIV reduced early systemic serum cytokine and chemokine responses to the vaccine, in stark contrast to MF59, where induction of a diverse immunomodulatory cytokine profile was observed in Southern African volunteers. Work on elucidating the differential effect of these two adjuvants on the types of innate immune cell responses in humans continues., OA18.03 E. Andersen-Nissen (1); V. Voillet (2); A. Naidoo (2); J. Kee (1); A. Fiore-Gartland (1); O. Dintwe (2); N. Grunenberg (1); L. Polakowski (3); L. Fleurs (4); I. Jani [...]

Background: The partially efficacious RV144 HIV-1 vaccine trial utilized a gp120 protein boost adjuvanted with alum, whereas the non-efficacious HVTN 702 preventive HIV vaccine utilized a gp120 protein boost adjuvanted with MF59. We compared Env-specific IgG and IgA responses in HVTN 107, a phase 1/2a partially double-blinded clinica trial, utilizing a Clade C ALVAC-HIV prime and 100 mcg gp120 protein boost adjuvanted with alum or MF59 vs. a protein-only boost. Methods: We randomized 132 participants into 4 groups and analyzed Env-specific IgG and IgA binding antibodies at Months 6.5 and 12 (NCT03284710). Results: Robust IgG (96.3% to 100%) and IgA (92% to 93%) responses were seen for all trial arms at the month 6.5 timepoint to gp120 Env proteins contained in the vaccine regimen (ZM96, TV1.C and 1086.C). Compared to all other trial arms, T3 (MF59-adjuvanted co-administration) exhibited significantly greater response rates and magnitudes to vaccine-matched Env proteins at the month 12 time-point. Comparable IgG response rates and magnitudes to vaccine-matched Env proteins were observed between the alum and MF59 prime-boost trial arms. Compared to other groups, T3 exhibited significantly higher IgG response rates to V1V2 panel antigens gp70_B.CaseA_V1V2 (83% vs. 18%-48%, p Conclusions: Env-specific antibody response rates between Alum and MF59-adjuvanted vaccine regimens were similar, including V1V2 IgG response rates that correlated with decreased HIV risk in RV144. On the other hand, co-administration of ALVAC-HIV with gp120 in MF59 induced the highest antibody response rates and magnitudes. Additional studies of vaccine-elicited antibody specificity and function will inform adjuvant-specific induction of potentially protective humoral immune responses., OA18.02 P. Goepfert (1); K. Mngadi (2); Z. Moodie (3); N. Grunenberg (3); J.J. Kee (3); K. Seaton (4); G. Tomaras (4); E. Andersen-Nissen (5); O. Dintwe (5); F. Laher [...]

Background. Proper handwashing can reduce the burden of diseases related to hand hygiene (HH) and so contribute reducing under-5 mortality. Preschoolers can benefit from HH interventions by the burden of disease and absenteeism being reduced. Objective. To perform a scoping review of literature to assess the types and effectiveness of HH interventions at preschools, with a view to providing a guideline for appropriate interventions for South African facilities. Methods. A literature search was conducted through the PubMed database to identify relevant studies. An iterative screening process to focus the review allowed for information on the type and effectiveness of interventions to be collated. An updated PubMed search was conducted to determine whether any interventions related to COVID-19 at preschools could be included. Results. No additional studies relating to COVID-19 were found. Of the 305 studies identified during the initial search, only 12 fitted the specific search criteria. Of these, 10 studies showed improvements in HH-related indicators following the interventions. Only two studies used health education as an intervention, whereas the others included the supply of HH products (to varying extents) as part of the intervention. Conclusion. HH interventions appear successful in reducing diseases spread by poor HH, improving general HH practices and reducing absenteeism among preschoolers. Studies using innovative, entertaining methods of educating children have shown to be successful in improving handwashing techniques and decreasing microbial growth on children's hands. HH interventions are suggested as an effective measure to improve HH during the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

South Africa is considered the murder capital of the world. The challenge for the South African government is to attract foreign investment to boost the economy in a country plagued by homicide. In this study, a change-point analysis was used to pinpoint significant changes in the murder trends in each of the nine provinces in South Africa from 2005 to 2015. This analysis will assist authorities to gain a better understanding of the big picture view in order to mitigate against this crime. Two methods were used in the analysis, namely, CUSUM and Bootstrap. CUSUM was used to analyse data trends, and Bootstrap was used to calculate the occurrence of change points based on the confidence level. The results of the analysis clearly show the abrupt shifts in murder data across the provinces of South Africa. In addition, we used the South African population statistic dataset from 2005 to 2015 to evaluate the relationship between population of the nine provinces and contextualise the murder crime rates year to year and province to province. [ABSTRACT FROM AUTHOR]

The experience of violent crime can have a significant impact on the physical and psychological well-being of victims and their families. This paper looks at household experience of violence in five impoverished sites in the city of Johannesburg, South Africa. Five sites were purposefully selected to reflect the prevailing housing profiles in settings of relative impoverishment in Johannesburg. A structured questionnaire was used to obtain information on demographic profiles, socioeconomic data, environmental conditions and health status. Bivariate analyses were conducted to assess the relationship between household experience of violence, and potential risk factors and health/social outcomes. Overall, members of 28% of households had been a victim of violence in the year preceding the study. Across sites, experience of violence within households ranged from 21% to 36%. Perceptions of drug abuse (p=0.01) and drug peddling (p=0.03) as being major problems in the neighbourhood, and living in a house of poor quality (p=0.01), were significantly associated with household experience of crime. In households with experience of violence, fear of crime (p=0.03) and depression (p<0.001) were elevated, and levels of exercise in men were decreased (p=0.05). This paper highlights the high prevalence of violence in impoverished urban areas in South Africa, and contributes to existing evidence regarding the associations between experience of violent crime and psychological ill health in affected communities. The high prevalence of violent crime, and the resultant health and social effects, demand a cross-sectoral intervention to reduce violence, with the health and social sectors playing key roles. [ABSTRACT FROM AUTHOR]

The standard-of-care (SOC) first-line treatment (1L) for R/M HNSCC consists of pembrolizumab (pembro) + platinum + fluorouracil (5-fluorouracil). However, 5-fluorouracil is associated with potential administration complications and related toxicity, creating the need for alternative chemotherapy combinations. The global, prospective phase 4 KEYNOTE-B10 study (NCT04489888) evaluated pembro + carboplatin (carbo) + paclitaxel (pacli) as 1L therapy for R/M HNSCC. Interim results of KEYNOTE-B10 showed promising antitumor activity for the initial 82 patients and manageable safety after a median follow-up of 8 months, suggesting that this 5-fluorouracil–free regimen could be a viable alternative for 1L R/M HNSCC. We report the protocol-specified final analysis including outcomes for all 101 enrolled patients. Patients with previously untreated R/M HNSCC, regardless of their PD-L1 status, were administered pembro 200 mg IV Q3W (≤35 cycles) and ≤6 cycles of pacli 100 mg/m2 IV Q1W (days 1 and 8) or 175 mg/m2 IV Q3W and carbo AUC 5 mg/mL/min IV Q3W until PD, intolerable toxicity, or patient withdrawal. The primary end point was ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary end points were DOR and PFS per RECIST v1.1 by BICR, OS, and safety. At February 20, 2023, data cutoff, treatment was ongoing for 15 patients (14.9%) while 86 (85.1%) discontinued treatment, primarily because of PD (n = 62, 61.4%). Median follow-up was 18.9 months (range, 9.1-27.0). Confirmed ORR by BICR was 48.5% (95% CI, 38.4-58.7); comprising 7 patients (6.9%) with confirmed CR and 42 (41.6%) with confirmed PR (table). Median (95% CI) PFS was 5.6 months (5.1-6.7), and OS was 13.1 months (9.6-15.2). Any-grade treatment-related adverse events (TRAEs) occurred in 96 patients (95.0%). Grade 3-5 TRAEs occurred in 76 patients (75.2%), most commonly decreased neutrophil count (44.6%) and anemia (19.8%). The promising efficacy and safety data obtained from the final analysis of the KEYNOTE-B10 trial suggest that pembro + carbo + pacli could be an additional treatment option to meet current clinical needs as a 1L therapy for R/M HNSCC. [ABSTRACT FROM AUTHOR]

BACKGROUND A safe, effective vaccine is essential to eradicating human immunodeficiency virus (HIV) infection. A canarypox-protein HIV vaccine regimen (ALVAC-HIV plus AIDSVAX B/E) showed modest efficacy in reducing infection in Thailand. An analogous regimen using HIV-1 subtype C virus showed potent humoral and cel-lular responses in a phase 1-2a trial in South Africa. Efficacy data and additional safety data were needed for this regimen in a larger population in South Africa. METHODS In this phase 2b-3 trial, we randomly assigned 5404 adults without HIV-1 infection to receive the vaccine (2704 participants) or placebo (2700 participants). The vaccine regimen consisted of injections ofALVAC-HIV at months 0 and 1, followed by four booster injections of ALVAC-HIV plus bivalent subtype C gpl20-MF59 adjuvant at months 3, 6, 12, and 18. The primary efficacy outcome was the occurrence of HIV-1 infection from randomization to 24 months. RESULTS In January 2020, prespecified criteria for nonefficacy were met at an interim analysis; further vaccinations were subsequently halted. The median age of the trial participants was 24 years; 70% of the participants were women. The incidence of adverse events was similar in the vaccine and placebo groups. During the 24-month followup, HIV-1 infection was diagnosed in 138 participants in the vaccine group and in 133 in the placebo group (hazard ratio, 1.02; 95% confidence interval, 0.81 to 1.30; P=0.84). CONCLUSIONS The ALVAC-gpl20 regimen did not prevent HIV-1 infection among participants in South Africa despite previous evidence ofimmunogenicity. (HVTN 702 ClinicalTrials .gov number, NCT02968849.). [ABSTRACT FROM AUTHOR]