Browsing by Subject "Vaccines"

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    The candidate TB vaccine, MVA85A, induces highly durable Th1 responses
    (Public Library of Science, 2014) Tameris, Michele; Geldenhuys, Hennie; Luabeya, Angelique KanyKany; Smit, Erica; Hughes, Jane E; Vermaak, Samantha; Hanekom, Willem A; Hatherill, Mark; Mahomed, Hassan; McShane, Helen; Scriba,Thomas J
    BACKGROUND: Vaccination against tuberculosis (TB) should provide long-term protective immunity against Mycobacterium tuberculosis ( M.tb ). The current TB vaccine, Bacille Calmette-Guerin (BCG), protects against disseminated childhood TB, but protection against lung TB in adolescents and adults is variable and mostly poor. One potential reason for the limited durability of protection may be waning of immunity through gradual attrition of BCG-induced T cells. We determined if a MVA85A viral-vector boost could enhance the durability of mycobacteria-specific T cell responses above those induced by BCG alone. METHODS: We describe a long-term follow-up study of persons previously vaccinated with MVA85A. We performed a medical history and clinical examination, a tuberculin skin test and measured vaccine-specific T cell responses in persons previously enrolled as adults, adolescents, children or infants into three different Phase II trials, between 2005 and 2011. RESULTS: Of 252 potential participants, 183 (72.6%) consented and completed the study visit. Vaccine-induced Ag85A-specific CD4+ T cell responses were remarkably persistent in healthy, HIV-uninfected adults, adolescents, children and infants, up to 6 years after MVA85A vaccination. Specific CD4+ T cells expressed surface markers consistent with either CD45RA−CCR7+ central memory or CD45RA−CCR7− effector memory T cells. Similarly durable Ag85A-specific CD4+ T cell responses were detected in HIV-infected persons who were on successful antiretroviral therapy when MVA85A was administered. By contrast, Ag85A-specific CD4+ T cell frequencies in untreated MVA85A-vaccinated HIV-infected persons were mostly undetectable 3-5 years after vaccination. CONCLUSION: MVA85A induces remarkably durable T cell responses in immunocompetent persons. However, results from a recent phase IIb trial of MVA85A, conducted in infants from the same geographic area and study population, showed no vaccine efficacy, suggesting that these durable T cell responses do not enhance BCG-induced protection against TB in infants.
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    Comparison of a real-time multiplex PCR and sequetyping assay for pneumococcal serotyping
    (Public Library of Science, 2015) Dube, Felix S; van Mens, Suzan P; Robberts, Lourens; Wolter, Nicole; Nicol, Paul; Mafofo, Joseph; Africa, Samantha; Zar, Heather J; Nicol, Mark P
    BACKGROUND: Pneumococcal serotype identification is essential to monitor pneumococcal vaccine effectiveness and serotype replacement. Serotyping by conventional serological methods are costly, labour-intensive, and require significant technical expertise. We compared two different molecular methods to serotype pneumococci isolated from the nasopharynx of South African infants participating in a birth cohort study, the Drakenstein Child Health Study, in an area with high 13-valent pneumococcal conjugate vaccine (PCV13) coverage. METHODS: A real-time multiplex PCR (rmPCR) assay detecting 21 different serotypes/-groups and a sequetyping assay, based on the sequence of the wzh gene within the pneumococcal capsular locus, were compared. Forty pneumococcal control isolates, with serotypes determined by the Quellung reaction, were tested. In addition, 135 pneumococcal isolates obtained from the nasopharynx of healthy children were tested by both serotyping assays and confirmed by Quellung testing. Discordant results were further investigated by whole genome sequencing of four isolates. RESULTS: Of the 40 control isolates tested, 25 had a serotype covered by the rmPCR assay. These were all correctly serotyped/-grouped. Sequetyping PCR failed in 7/40 (18%) isolates. For the remaining isolates, sequetyping assigned the correct serotype/-group to 29/33 (88%) control isolates. Of the 132/135 (98%) nasopharyngeal pneumococcal isolates that could be typed, 69/132 (52%) and 112/132 (85%) were assigned the correct serotype/-group by rmPCR and sequetyping respectively. The serotypes of 63/132 (48%) isolates were not included in the rmPCR panel. All except three isolates (serotype 25A and 38) were theoretically amplified and differentiated into the correct serotype/-group with some strains giving ambigous results (serotype 13/20, 17F/33C, and 11A/D/1818F). Of the pneumococcal serotypes detected in this study, 69/91 (76%) were not included in the current PCV13. The most frequently identified serotypes were 11A, 13, 15B/15C, 16F and 10A. CONCLUSION: The rmPCR assay performed well for the 21 serotypes/-groups included in the assay. However, in our study setting, a large proportion of serotypes were not detected by rmPCR. The sequetyping assay performed well, but did misassign specific serotypes. It may be useful for regions where vaccine serotypes are less common, however confirmatory testing is advisable.
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    Continued follow-up of Phambili Phase 2b randomized HIV-1 vaccine trial participants supports increased HIV-1 acquisition among vaccinated men
    (Public Library of Science, 2015) Moodie, Zoe; Metch, Barbara; Bekker, Linda-Gail; Churchyard, Gavin; Nchabeleng, Maphoshane; Mlisana, Koleka; Laher, Fatima; Roux, Surita; Mngadi, Kathryn; Innes, Craig
    BACKGROUND: The Phase 2b double-blinded, randomized Phambili/HVTN 503 trial evaluated safety and efficacy of the MRK Ad5 gag / pol / nef subtype B HIV-1 preventive vaccine vs placebo in sexually active HIV-1 seronegative participants in South Africa. Enrollment and vaccinations stopped and participants were unblinded but continued follow-up when the Step study evaluating the same vaccine in the Americas, Caribbean, and Australia was unblinded for non-efficacy. Final Phambili analyses found more HIV-1 infections amongst vaccine than placebo recipients, impelling the HVTN 503-S recall study. METHODS: HVTN 503-S sought to enroll all 695 HIV-1 uninfected Phambili participants, provide HIV testing, risk reduction counseling, physical examination, risk behavior assessment and treatment assignment recall. After adding HVTN 503-S data, HIV-1 infection hazard ratios (HR vaccine vs. placebo) were estimated by Cox models. RESULTS: Of the 695 eligible, 465 (67%) enrolled with 230 from the vaccine group and 235 from the placebo group. 38% of the 184 Phambili dropouts were enrolled. Enrollment did not differ by treatment group, gender, or baseline HSV-2. With the additional 1286 person years of 503-S follow-up, the estimated HR over Phambili and HVTN 503-S follow-up was 1.52 (95% CI 1.08-2.15, p = 0.02, 82 vaccine/54 placebo infections). The HR was significant for men (HR = 2.75, 95% CI 1.49, 5.06, p = 0.001) but not for women (HR = 1.12, 95% CI 0.73, 1.72, p = 0.62). CONCLUSION: The additional follow-up from HVTN 503-S supported the Phambili finding of increased HIV-1 acquisition among vaccinated men and strengthened the evidence of lack of vaccine effect among women. Trial Registration clinicaltrials.gov NCT00413725 SA National Health Research Database DOH-27-0207-1539
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    Dendritic cell-mediated vaccination relies on interleukin-4 receptor signaling to avoid tissue damage after Leishmania major infection of BALB/c mice
    (Public Library of Science, 2012) Masic, Anita; Hurdayal, Ramona; Nieuwenhuizen, Natalie E; Brombacher, Frank; Moll, Heidrun
    Prevention of tissue damages at the site of Leishmania major inoculation can be achieved if the BALB/c mice are systemically given L. major antigen (LmAg)-loaded bone marrow-derived dendritic cells (DC) that had been exposed to CpG-containing oligodeoxynucleotides (CpG ODN). As previous studies allowed establishing that interleukin-4 (IL-4) is involved in the redirection of the immune response towards a type 1 profile, we were interested in further exploring the role of IL-4. Thus, wild-type (wt) BALB/c mice or DC-specific IL-4 receptor alpha (IL-4Rα)-deficient (CD11ccreIL-4Rα−/lox) BALB/c mice were given either wt or IL-4Rα-deficient LmAg-loaded bone marrow-derived DC exposed or not to CpG ODN prior to inoculation of 2×105 stationary-phase L. major promastigotes into the BALB/c footpad. The results provide evidence that IL4/IL-4Rα-mediated signaling in the vaccinating DC is required to prevent tissue damage at the site of L. major inoculation, as properly conditioned wt DC but not IL-4Rα-deficient DC were able to confer resistance. Furthermore, uncontrolled L. major population size expansion was observed in the footpad and the footpad draining lymph nodes of CD11ccreIL-4Rα−/lox mice immunized with CpG ODN-exposed LmAg-loaded IL-4Rα-deficient DC, indicating the influence of IL-4Rα-mediated signaling in host DC to control parasite replication. In addition, no footpad damage occurred in BALB/c mice that were systemically immunized with LmAg-loaded wt DC doubly exposed to CpG ODN and recombinant IL-4. We discuss these findings and suggest that the IL4/IL4Rα signaling pathway could be a key pathway to trigger when designing vaccines aimed to prevent damaging processes in tissues hosting intracellular microorganisms.
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    Epstein-Barr virus but not cytomegalovirus is associated with reduced vaccine antibody responses in Gambian infants
    (Public Library of Science, 2010) Holder, Beth; Miles, David J C; Kaye, Steve; Crozier, Sarah; Mohammed, Nuredin Ibrahim; Duah, Nancy O; Roberts, Elishia; Ojuola, Olubukola; Palmero, Melba S; Touray, Ebrima S
    BACKGROUND: Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are persistent herpesviruses that have various immunomodulatory effects on their hosts. Both viruses are usually acquired in infancy in Sub-Saharan Africa, a region where childhood vaccines are less effective than in high income settings. To establish whether there is an association between these two observations, we tested the hypothesis that infection with one or both viruses modulate antibody responses to the T-cell independent meningococcal polysaccharide vaccine and the T-cell dependent measles vaccines. METHODOLOGY/PRINCIPAL FINDINGS: Infection with EBV and CMV was diagnosed by the presence of virus-specific IgM in the peripheral blood or by the presence of IgG at higher levels than that found in umbilical cord blood. Anti-meningococcus IgG and IgM were quantified by ELISA. Anti-measles antibody responses were quantified by haemagglutinin antibody inhibition assay. Infants infected with EBV had reduced IgG and IgM antibody responses to meningococcal polysaccharides and to measles vaccine. Infection with CMV alone predicted no changes in the response to meningococcal polysaccharide. While CMV alone had no discernable effect on the antibody response to measles, the response of infants infected with both CMV and EBV was similar to that of infants infected with neither, suggesting that the effects of CMV infection countered the effects of EBV on measles antibody responses. CONCLUSIONS: The results of this exploratory study indicate that infection with EBV is associated with reduced antibody responses to polysaccharides and to measles vaccine, but suggest that the response to T-cell dependent antigens such as measles haemagglutinin may be restored by infection with CMV.
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    Features of recently transmitted HIV-1 clade C viruses that impact antibody recognition: implications for active and passive immunization
    (Public Library of Science, 2016) Rademeyer, Cecilia; Korber, Bette; Seaman, Michael S; Giorgi, Elena E; Thebus, Ruwayhida; Robles, Alexander; Sheward, Daniel J; Wagh, Kshitij; Garrity, Jetta; Carey, Brittany R; Gao, Hongmei; Greene, Kelli M; Tang, Haili; Bandawe, Gama P; Marais, Jinny C; Diphoko, Thabo E; Hraber, Peter; Tumba, Nancy; Moore, Penny L; Gray, Glenda E; Kublin, James; McElrath, M Juliana; Vermeulen, Marion; Middelkoop, Keren; Bekker, Linda-Gail; Hoelscher, Michael; Maboko, Leonard; Makhema, Joseph; Robb, Merlin L; Karim, Salim Abdool; Karim, Quarraisha Abdool; Kim, Jerome H; Hahn, Beatrice H; Gao, Feng; Swanstrom, Ronald; Morris, Lynn; Montefiori, David C; Williamson, Carolyn
    Author Summary: Vaccine and passive immunization prophylactic trials that rely on antibody-mediated protection are planned for HIV-1 clade C epidemic regions of southern Africa, which have amongst the highest HIV-1 incidences globally. This includes a phase 2b trial of passively administered monoclonal antibody, VRC01; as well as a phase 3 trial using the clade C modified version of the partially efficacious RV144 vaccine. The extraordinary diversity of HIV-1 poses a major obstacle to these interventions, and our study aimed to determine the implications of viral diversity on antibody recognition. Investigations using our panel of very early viruses augment current knowledge of vulnerable targets on transmitted viruses for vaccine design and passive immunization studies. Evidence of antigenic drift with viruses becoming more resistant over time suggests that these prevention modalities will need to be updated over time and that combinations of antibodies will be necessary to achieve coverage in passive immunization studies. We further show that it may be more difficult to obtain protection in the genetically diverse clade C epidemic compared to RV144 where the epidemic is less diverse, although it should be noted that the correlates of infection risk are yet to be defined in the clade C setting.
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    High burden of human papillomavirus (HPV) infection among young women in KwaZulu-Natal, South Africa
    (Public Library of Science, 2016) Ebrahim, Sumayyah; Mndende, Xolani K; Kharsany, Ayesha B M; Mbulawa, Zizipho Z A; Naranbhai, Vivek; Frohlich, Janet; Werner, Lise; Samsunder, Natasha; Karim, Quarraisha Abdool; Williamson, Anna-Lise
    Objectives HPV infection causes cervical cancer, yet information on prevalence and risk factors for HPV in Africa remain sparse. This study describes the prevalence of HPV genotypes and risk factors associated with HPV among young women ≤ 30 years of age in KwaZulu-Natal (KZN), South Africa. METHODS: Cervicovaginal lavage samples were tested for HPV genotypes in 224 women enrolled in a prospective cohort study. Clinical, behavioural and demographic data were collected. We measured prevalence of HPV genotypes and using logistic regression, examined for factors associated with HPV. RESULTS: Median age of participants was 21 years [interquartile range (IQR):18-23]. The overall prevalence of HPV was 76.3% (171/224) with multiple and single genotypes prevalent in 56.3% and 20.1% of women respectively. Proportion of women with high-risk genotypes (16, 18, 31, 33, 35, 39, 45, 51, 52, 56 and 58) was 54.5%. Women not living with their partner [adjusted odds ratio (aOR)] = 3.42 95% CI1.22-9.60; p = 0.019), was significantly associated with HPV infection and high-risk HPV genotype infection. CONCLUSION: The high burden of HPV and associated risk behaviours highlight the need to intensify behavioural interventions to prevent HPV acquisition in young women. The large scale delivery of HPV vaccine should be prioritised to prevent HPV acquisition and reduce HPV-related morbidity.
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    HIV-1 subtype C mosaic Gag expressed by BCG and MVA elicits persistent effector t cell responses in a prime-boost regimen in mice
    (Public Library of Science, 2016) Jongwe, Tsungai Ivai; Chapman, Ros; Douglass, Nicola; Chetty, Shivan; Chege, Gerald; Williamson, Anna-Lise
    Over 90% of HIV/AIDS positive individuals in sub-Saharan Africa are infected with highly heterogeneous HIV-1 subtype C (HIV-1C) viruses. One of the best ways to reduce the burden of this disease is the development of an affordable and effective prophylactic vaccine. Mosaic immunogens are computationally designed to overcome the hurdle of HIV diversity by maximizing the expression of potential T cell epitopes. Mycobacterium bovis BCG Δ panCD auxotroph and modified vaccinia Ankara (MVA) vaccines expressing HIV-1C mosaic Gag (Gag M ) were tested in a prime-boost regimen to demonstrate immunogenicity in a mouse study. The BCG-Gag M vaccine was stable and persisted 11.5 weeks post vaccination in BALB/c mice. Priming with BCG-Gag M and boosting with MVA-Gag M elicited higher Gag-specific IFN-γ ELISPOT responses than the BCG-Gag M only and MVA-Gag M only homologous vaccination regimens. The heterologous vaccination also generated a more balanced and persistent CD4 + and CD8 + T cell Gag-specific IFN-γ ELISPOT response with a predominant effector memory phenotype. A Th1 bias was induced by the vaccines as determined by the predominant secretion of IFN-γ, TNF-α, and IL-2. This study shows that a low dose of MVA (10 4 pfu) can effectively boost a BCG prime expressing the same mosaic immunogen, generating strong, cellular immune responses against Gag in mice. Our data warrants further evaluation in non-human primates. A low dose vaccine would be an advantage in the resource limited countries of sub-Saharan Africa and India (where the predominating virus is HIV-1 subtype C).
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    Individual and contextual factors associated with low childhood immunisation coverage in sub-Saharan Africa: a multilevel analysis
    (Public Library of Science, 2012) Wiysonge, Charles S; Uthman, Olalekan A; Ndumbe, Peter M; Hussey, Gregory D
    BACKGROUND: In 2010, more than six million children in sub-Saharan Africa did not receive the full series of three doses of the diphtheria-tetanus-pertussis vaccine by one year of age. An evidence-based approach to addressing this burden of un-immunised children requires accurate knowledge of the underlying factors. We therefore developed and tested a model of childhood immunisation that includes individual, community and country-level characteristics. Method and FINDINGS: We conducted multilevel logistic regression analysis of Demographic and Health Survey data for 27,094 children aged 12-23 months, nested within 8,546 communities from 24 countries in sub-Saharan Africa. According to the intra-country and intra-community correlation coefficient implied by the estimated intercept component variance, 21% and 32% of the variance in unimmunised children were attributable to country- and community-level factors respectively. Children born to mothers (OR 1.35, 95%CI 1.18 to 1.53) and fathers (OR 1.13, 95%CI 1.12 to 1.40) with no formal education were more likely to be unimmunised than those born to parents with secondary or higher education. Children from the poorest households were 36% more likely to be unimmunised than counterparts from the richest households. Maternal access to media significantly reduced the odds of children being unimmunised (OR 0.94, 95%CI 0.94 to 0.99). Mothers with health seeking behaviours were less likely to have unimmunised children (OR 0.56, 95%CI 0.54 to 0.58). However, children from urban areas (OR 1.12, 95% CI 1.01 to 1.23), communities with high illiteracy rates (OR 1.13, 95% CI 1.05 to 1.23), and countries with high fertility rates (OR 4.43, 95% CI 1.04 to 18.92) were more likely to be unimmunised. CONCLUSION: We found that individual and contextual factors were associated with childhood immunisation, suggesting that public health programmes designed to improve coverage of childhood immunisation should address people, and the communities and societies in which they live.
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    Is obesity a risk factor for vaccine non-responsiveness?
    (Public Library of Science, 2013) Young, Katherine M; Gray, Clive M; Bekker, Linda-Gail
    Understanding the link between vaccine immunogenicity and efficacy is currently a major focus in HIV research. Consequently, recent developments in the HIV-1 vaccine field have led to a closer look at immune responses to known efficacious vaccines. We undertook a study to explore clinical predictors of vaccine efficacy following recombinant hepatitis B (rHBV) vaccination in a cohort of HIV-uninfected, hepatitis B virus naïve women living in a peri-urban setting in Cape Town. Our aim was to define host biological risk factors associated with lack of vaccine uptake. We found a significant association (p=0.009) between body mass index (BMI) and lack of vaccine-specific IgG titre (<10mIU/mL). Obese individuals (BMI ≥ 30kg/m 2 ) were significantly more likely to be non-responders following 2 rHBV vaccine doses (Adjusted Odds Ratio of 8.75; p=0.043). There was no observed association between vaccine responses and age, method of contraception or time from vaccination to antibody measurement. These data suggest that obesity-associated factors interfere with vaccine immunogenicity and possible efficacy.
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    Isolation of Non-Tuberculous Mycobacteria in Children Investigated for Pulmonary Tuberculosis
    (Public Library of Science, 2006) Hatherill, Mark; Hawkridge, Tony; Whitelaw, Andrew; Tameris, Michele; Mahomed, Hassan; Moyo, Sizulu; Hanekom, Willem; Hussey, Gregory
    Objective To evaluate the frequency and clinical significance of non-tuberculous mycobacteria (NTM) isolates among children investigated for pulmonary tuberculosis in a rural South African community. METHODS: Children were investigated for pulmonary tuberculosis as part of a tuberculosis vaccine surveillance program (2001-2005). The clinical features of children in whom NTM were isolated, from induced sputum or gastric lavage, were compared to those with culture-proven M. tuberculosis . RESULTS: Mycobacterial culture demonstrated 114 NTM isolates from 109 of the 1,732 children investigated, a crude yield of 6% (95% CI 5-7). The comparative yield of positive NTM cultures from gastric lavage was 40% (95% CI 31-50), compared to 67% (95% CI 58-76) from induced sputum. 95% of children with NTM isolates were symptomatic. Two children were HIV-infected. By contrast, M. tuberculosis was isolated in 187 children, a crude yield of 11% (95% CI 9-12). Compared to those with culture-proven M. tuberculosis , children with NTM isolates were less likely to demonstrate acid-fast bacilli on direct smear microscopy (OR 0.19; 95% 0.0-0.76). Children with NTM were older (p<0.0001), and more likely to demonstrate constitutional symptoms (p = 0.001), including fever (p = 0.003) and loss of weight or failure to gain weight (p = 0.04), but less likely to demonstrate a strongly positive tuberculin skin test (p<0.0001) or radiological features consistent with pulmonary tuberculosis (p = 0.04). DISCUSSION: NTM were isolated in 6% of all children investigated for pulmonary tuberculosis and in more than one third of those with a positive mycobacterial culture. NTM may complicate the diagnosis of PTB in regions that lack capacity for mycobacterial species identification. The association of NTM isolates with constitutional symptoms suggestive of host recognition requires further investigation.
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    Myeloid derived suppressor cells are present at high frequency in neonates and suppress in vitro T cell responses
    (Public Library of Science, 2014) Gervassi, Ana; Lejarcegui, Nicholas; Dross, Sandra; Jacobson, Amanda; Itaya, Grace; Kidzeru, Elvis; Gantt, Soren; Jaspan, Heather; Horton, Helen
    Over 4 million infants die each year from infections, many of which are vaccine-preventable. Young infants respond relatively poorly to many infections and vaccines, but the basis of reduced immunity in infants is ill defined. We sought to investigate whether myeloid-derived suppressor cells (MDSC) represent one potential impediment to protective immunity in early life, which may help inform strategies for effective vaccination prior to pathogen exposure. We enrolled healthy neonates and children in the first 2 years of life along with healthy adult controls to examine the frequency and function of MDSC, a cell population able to potently suppress T cell responses. We found that MDSC, which are rarely seen in healthy adults, are present in high numbers in neonates and their frequency rapidly decreases during the first months of life. We determined that these neonatal MDSC are of granulocytic origin (G-MDSC), and suppress both CD4+ and CD8+ T cell proliferative responses in a contact-dependent manner and gamma interferon production. Understanding the role G-MDSC play in infant immunity could improve vaccine responsiveness in newborns and reduce mortality due to early-life infections.
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    A phase IIA randomized clinical trial of a multiclade HIV-1 DNA prime followed by a multiclade rAd5 HIV-1 vaccine boost in healthy adults (HVTN204)
    (Public Library of Science, 2011) Churchyard, Gavin J; Morgan, Cecilia; Adams, Elizabeth; Hural, John; Graham, Barney S; Moodie, Zoe; Grove, Doug; Gray, Glenda; Bekker, Linda-Gail; McElrath, M Juliana
    BACKGROUND: The safety and immunogenicity of a vaccine regimen consisting of a 6-plasmid HIV-1 DNA prime (envA, envB, envC, gagB, polB, nefB) boosted by a recombinant adenovirus serotype-5 (rAd5) HIV-1 with matching inserts was evaluated in HIV-seronegative participants from South Africa, United States, Latin America and the Caribbean. METHODS: 480 participants were evenly randomized to receive either: DNA (4 mg IM by Biojector) at 0, 1 and 2 months, followed by rAd5 (10 10 PU IM by needle/syringe) at 6 months; or placebo. Participants were monitored for reactogenicity and adverse events throughout the 12-month study. Peak and duration of HIV-specific humoral and cellular immune responses were evaluated after the prime and boost. RESULTS: The vaccine was well tolerated and safe. T-cell responses, detected by interferon-γ (IFN-γ) ELISpot to global potential T-cell epitopes (PTEs) were observed in 70.8% (136/192) of vaccine recipients overall, most frequently to Gag (54.7%) and to Env (54.2%). In U.S. vaccine recipients T-cell responses were less frequent in Ad5 sero-positive versus sero-negative vaccine recipients (62.5% versus 85.7% respectively, p = 0.035). The frequency of HIV-specific CD4+ and CD8+ T-cell responses detected by intracellular cytokine staining were similar (41.8% and 47.2% respectively) and most secreted ≥2 cytokines. The vaccine induced a high frequency (83.7%-94.6%) of binding antibody responses to consensus Group M, and Clades A, B and C gp140 Env oligomers. Antibody responses to Gag were elicited in 46% of vaccine recipients. CONCLUSION: The vaccine regimen was well-tolerated and induced polyfunctional CD4+ and CD8+ T-cells and multi-clade anti-Env binding antibodies. Trial Registration: ClinicalTrials.gov NCT00125970
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    Predictors of HVTN 503 MRK-AD5 HIV-1 gag/pol/nef vaccine Induced immune responses
    (Public Library of Science, 2014) Hopkins, Kathryn L; Laher, Fatima; Otwombe, Kennedy; Churchyard, Gavin; Bekker, Linda-Gail; DeRosa, Stephen; Nchabeleng, Maphoshane; Mlisana, Koleka; Kublin, James; Gray, Glenda
    BACKGROUND: Phambili, the Merck (MRK)-Adenovirus Type 5 (Ad5) HIV-1 gag/pol/nef subtype B vaccine study, conducted in South Africa, suspended enrollment and vaccination when companion study, Step, was found non-efficacious. Although the vaccine did not prevent HIV-1 infection or lower viral-load setpoint, immune responses recognized clades B and C HIV-1 subtypes. We investigated predictors of the vaccine-induced antigen-specific immune responses. METHODS: Vaccine-induced immunogenicity was ascertained by interferon-γ ELISpot assays on the first 186 enrolled participants receiving two vaccinations. Analyses, stratified by study arm/sex, were performed on baseline demographics [sex, age, Body Mass Index (BMI), site, Adenovirus Type-5 (Ad5) titer, Herpes Simplex Virus Type-2 (HSV2) status, heavy drinking]. Multivariate logistic regression determined predictors. RESULTS: Of the 186 participants, 53.7% (n = 100) were female, median BMI was 22.5 [IQR: 20.4-27.0], 85.5% (n = 159) were Ad5 seropositive, and 18.8% (n = 35) drank heavily. All vaccine recipients responded to both clade B (n = 87; 47%) and/or C (n = 74; 40%), p = 0.17. In multivariate analysis, female sex [Adjusted Odds Ratio (AOR): 6.478; p = 0.0159], overweight/obese BMI (AOR: 0.186; p = 0.0452), and heavy drinking (AOR: 0.270; p = 0.048) significantly predicted immune response to clade C for any antigens. A marginally significant predictor of clade C-pol antigen was female sex (AOR: 3.182; p = 0.0500). CONCLUSIONS: Sex, BMI, and heavy drinking affected vaccine-induced HIV-1 specific immune responses to clade C antigens. The role of female sex and overweight/obese BMI boosting and suppressing vaccine-induced HIV-1 specific immune responses, respectively, requires elucidation, including any effect on HIV vaccine efficacy, especially in the era of colliding epidemics (HIV and obesity).
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    Pregnancy incidence and correlates during the HVTN 503 Phambili HIV vaccine trial conducted among South African women
    (Public Library of Science, 2012) Latka, Mary H; Fielding, Katherine; Gray, Glenda E; Bekker, Linda-Gail; Nchabeleng, Maphoshane; Mlisana, Koleka; Nielson, Tanya; Roux, Surita; Mkhize, Baningi; Mathebula, Matsontso
    BACKGROUND: HIV prevention trials are increasingly being conducted in sub-Saharan Africa. Women at risk for HIV are also at risk of pregnancy. To maximize safety, women agree to avoid pregnancy during trials, yet pregnancies occur. Using data from the HVTN 503/"Phambili" vaccine trial, we report pregnancy incidence during and after the vaccination period and identify factors, measured at screening, associated with incident pregnancy. METHODS: To enrol in the trial, women agreed and were supported to avoid pregnancy until 1 month after their third and final vaccination ("vaccination period"), corresponding to the first 7 months of follow-up. Unsterilized women, pooled across study arms, were analyzed. Poisson regression compared pregnancy rates during and after the vaccination period. Cox proportional hazards regression identified associations with first pregnancy. RESULTS: Among 352 women (median age 23 yrs; median follow-up 1.5 yrs), pregnancy incidence was 9.6/100 women-years overall and 6.8/100 w-yrs and 11.3/100 w-yrs during and after the vaccination period, respectively [Rate Ratio = 0.60 (0.32-1.14), p = 0.10]. In multivariable analysis, pregnancy was reduced among women who: enrolled at sites providing contraception on-site [HR = 0.43, 95% CI (0.22-0.86)]; entered the trial as injectable contraceptive users [HR = 0.37 (0.21-0.67)] or as consistent condom users (trend) [HR = 0.54 (0.28-1.04)]. Compared with women with a single partner of HIV-unknown status, pregnancy rates were increased among women with: a single partner whose status was HIV-negative [HR = 2.34(1.16-4.73)] and; 2 partners both of HIV-unknown status [HR = 4.42(1.59-12.29)]. Women with 2 more of these risk factors: marijuana use, heavy drinking, or use of either during sex, had increased pregnancy incidence [HR = 2.66 (1.24-5.72)]. CONCLUSIONS: It is possible to screen South African women for pregnancy risk at trial entry. Providing injectable contraception for free on-site and supporting consistent condom use may reduce incident pregnancy. Screening should determine the substance use, partnering, and HIV status of both members of the couple for both pregnancy and HIV prevention. Trial Registration SA National Health Research Database DOH-27-0207-1539; Clinicaltrials.gov NCT00413725
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    Priming with a recombinant pantothenate auxotroph of Mycobacterium bovis BCG and boosting with MVA elicits HIV-1 Gag specific CD8+ T cells
    (Public Library of Science, 2012) Chapman, Rosamund; Shephard, Enid; Stutz, Helen; Douglass, Nicola; Sambandamurthy, Vasan; Garcia, Irene; Ryffel, Bernhard; Jacobs, William; Williamson, Anna-Lise
    A safe and effective HIV vaccine is required to significantly reduce the number of people becoming infected with HIV each year. In this study wild type Mycobacterium bovis BCG Pasteur and an attenuated pantothenate auxotroph strain (BCGΔ panCD ) that is safe in SCID mice, have been compared as vaccine vectors for HIV-1 subtype C Gag. Genetically stable vaccines BCG[pHS400] (BCG-Gag) and BCGΔ panCD [pHS400] (BCGpan-Gag) were generated using the Pasteur strain of BCG, and a panothenate auxotroph of Pasteur respectively. Stability was achieved by the use of a codon optimised gag gene and deletion of the hsp60-lysA promoter-gene cassette from the episomal vector pCB119. In this vector expression of gag is driven by the mtrA promoter and the Gag protein is fused to the Mycobacterium tuberculosis 19 kDa signal sequence. Both BCG-Gag and BCGpan-Gag primed the immune system of BALB/c mice for a boost with a recombinant modified vaccinia virus Ankara expressing Gag (MVA-Gag). After the boost high frequencies of predominantly Gag-specific CD8 + T cells were detected when BCGpan-Gag was the prime in contrast to induction of predominantly Gag-specific CD4 + T cells when priming with BCG-Gag. The differing Gag-specific T-cell phenotype elicited by the prime-boost regimens may be related to the reduced inflammation observed with the pantothenate auxotroph strain compared to the parent strain. These features make BCGpan-Gag a more desirable HIV vaccine candidate than BCG-Gag. Although no Gag-specific cells could be detected after vaccination of BALB/c mice with either recombinant BCG vaccine alone, BCGpan-Gag protected mice against a surrogate vaccinia virus challenge.
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    Priming with recombinant auxotrophic BCG expressing HIV-1 Gag, RT and Gp120 and boosting with recombinant MVA induces a robust T cell response in mice
    (Public Library of Science, 2013) Chapman, Rosamund; Stutz, Helen; Jr, William Jacobs; Shephard, Enid; Williamson, Anna-Lise
    In previous studies we have shown that a pantothenate auxotroph of Myocbacterium bovis BCG (BCGΔ panCD ) expressing HIV-1 subtype C Gag induced Gag-specific immune responses in mice and Chacma baboons after prime-boost immunization in combination with matched rMVA and VLP vaccines respectively. In this study recombinant BCG (rBCG) expressing HIV-1 subtype C reverse transcriptase and a truncated envelope were constructed using both the wild type BCG Pasteur strain as a vector and the pantothenate auxotroph. Mice were primed with rBCG expressing Gag and RT and boosted with a recombinant MVA, expressing a polyprotein of Gag, RT, Tat and Nef (SAAVI MVA-C). Priming with rBCGΔ panCD expressing Gag or RT rather than the wild type rBCG expressing Gag or RT resulted in higher frequencies of total HIV-specific CD8 + T cells and increased numbers of T cells specific to the subdominant Gag and RT epitopes. Increasing the dose of rBCG from 10 5 cfu to 10 7 cfu also led to an increase in the frequency of responses to subdominant HIV epitopes. A mix of the individual rBCGΔ panCD vaccines expressing either Gag, RT or the truncated Env primed the immune system for a boost with SAAVI MVA-C and generated five-fold higher numbers of HIV-specific IFN-γ-spot forming cells than mice primed with rBCGΔ panCD containing an empty vector control. Priming with the individual rBCGΔ panCD vaccines or the mix and boosting with SAAVI MVA-C also resulted in the generation of HIV-specific CD4 + and CD8 + T cells producing IFN-γ and TNF-α and CD4 + cells producing IL-2. The rBCG vaccines tested in this study were able to prime the immune system for a boost with rMVA expressing matching antigens, inducing robust, HIV-specific T cell responses to both dominant and subdominant epitopes in the individual proteins when used as individual vaccines or in a mix.
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    A qualitative analysis of factors influencing HPV vaccine uptake in Soweto, South Africa among adolescents and their caregivers
    (Public Library of Science, 2013) Katz, Ingrid T; Nkala, Busisiwe; Dietrich, Janan; Wallace, Melissa; Bekker, Linda-Gail; Pollenz, Kathryn; Bogart, Laura M; Wright, Alexi A; Tsai, Alexander C; Bangsberg, David R
    BACKGROUND: In South Africa, the prevalence of oncogenic Human Papillomavirus (HPV) may be as high as 64%, and cervical cancer is the leading cause of cancer-related death among women. The development of efficacious prophylactic vaccines has provided an opportunity for primary prevention. Given the importance of psycho-social forces in vaccine uptake, we sought to elucidate factors influencing HPV vaccination among a sample of low-income South African adolescents receiving the vaccine for the first time in Soweto. METHODS: The HPV vaccine was introduced to adolescents in low-income townships throughout South Africa as part of a nationwide trial to understand adolescent involvement in future vaccine research targeting human immunodeficiency virus (HIV). We performed in-depth semi-structured interviews with purposively-sampled adolescents and their care providers to understand what forces shaped HPV vaccine uptake. Interviews were recorded, transcribed, translated, and examined using thematic analysis. RESULTS: Of 224 adolescents recruited, 201 initiated the vaccine; 192 (95.5%) received a second immunization; and 164 (81.6%) completed three doses. In our qualitative study of 39 adolescent-caregiver dyads, we found that factors driving vaccine uptake reflected a socio-cultural backdrop of high HIV endemnicity, sexual violence, poverty, and an abundance of female-headed households. Adolescents exercised a high level of autonomy and often initiated decision-making. Healthcare providers and peers provided support and guidance that was absent at home. The impact of the HIV epidemic on decision-making was substantial, leading participants to mistakenly conflate HPV and HIV. CONCLUSIONS: In a setting of perceived rampant sexual violence and epidemic levels of HIV, adolescents and caregivers sought to decrease harm by seeking a vaccine targeting a sexually transmitted infection (STI). Despite careful consenting, there was confusion regarding the vaccine's target. Future interventions promoting STI vaccines will need to provide substantial information for participants, particularly adolescents who may exercise a significant level of autonomy in decision-making.
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    A quantitative analysis of complexity of human pathogen-specific CD4 T cell responses in healthy M. tuberculosis infected South Africans
    (Public Library of Science, 2016) Arlehamn, Cecilia S Lindestam; McKinney, Denise M; Carpenter, Chelsea; Paul, Sinu; Rozot, Virginie; Makgotlho, Edward; Gregg, Yolande; Van Rooyen, Michele; Ernst, Joel D; Hatherill, Mark; Hanekom, Willem A; Peters, Bjoern; Scriba, Thomas J; Sette, Alessandro
    Author Summary: Human pathogen-specific immune responses are tremendously complex and the techniques to study them ever expanding. There is an urgent need for a quantitative analysis and better understanding of pathogen-specific immune responses. Mycobacterium tuberculosis (Mtb) is one of the leading causes of mortality due to an infectious agent worldwide. Here, we were able to quantify the Mtb-specific response in healthy individuals with Mtb infection from South Africa. The response is highly diverse and 66 epitopes are required to capture 80% of the total reactivity. Our study also show that the majority of the identified epitopes are restricted by multiple HLA alleles. Thus, technical advances are required to capture and characterize the complete pathogen-specific response. This study demonstrates further that the approach combining identified epitopes into "megapools" allows capturing a large fraction of the total reactivity. This suggests that this technique is generally applicable to the characterization of immunity to other complex pathogens. Together, our data provide for the first time a quantitative analysis of the complex pathogen-specific T cell response and provide a new understanding of human infections in a natural infection setting.
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    Sequential Immunization with gp140 boosts immune responses primed by modified vaccinia Ankara or DNA in HIV-uninfected South African participants
    (Public Library of Science, 2016) Churchyard, Gavin; Mlisana, Koleka; Karuna, Shelly; Williamson, Anna-Lise; Williamson, Carolyn; Morris, Lynn; Tomaras, Georgia D; De Rosa, Stephen C; Gilbert, Peter B; Gu, Niya; Yu, Chenchen; Mkhize, Nonhlanhla N; Hermanus, Tandile; Allen, Mary; Pensiero, Michael; Barnett, Susan W; Gray, Glenda; Bekker, Linda-Gail; Montefiori, David C; Kublin, James; Corey, Lawrence
    BACKGROUND: The safety and immunogenicity of SAAVI DNA-C2 (4 mg IM), SAAVI MVA-C (2.9 x 10 9 pfu IM) and Novartis V2-deleted subtype C gp140 (100 mcg) with MF59 adjuvant in various vaccination regimens was evaluated in HIV-uninfected adults in South Africa. METHODS: Participants at three South African sites were randomized (1:1:1:1) to one of four vaccine regimens: MVA prime, sequential gp140 protein boost (M/M/P/P); concurrent MVA/gp140 (MP/MP); DNA prime, sequential MVA boost (D/D/M/M); DNA prime, concurrent MVA/gp140 boost (D/D/MP/MP) or placebo. Peak HIV specific humoral and cellular responses were measured. RESULTS: 184 participants were enrolled: 52% were female, all were Black/African, median age was 23 years (range, 18-42 years) and 79% completed all vaccinations. 159 participants reported at least one adverse event, 92.5% were mild or moderate. Five, unrelated, serious adverse events were reported. The M/M/P/P and D/D/MP/MP regimens induced the strongest peak neutralizing and binding antibody responses and the greatest CD4+ T-cell responses to Env. All peak neutralizing and binding antibody responses decayed with time. The MVA, but not DNA, prime contributed to the humoral and cellular immune responses. The D/D/M/M regimen was poorly immunogenic overall but did induce modest CD4+ T-cell responses to Gag and Pol. CD8+ T-cell responses to any antigen were low for all regimens. CONCLUSIONS: The SAAVI DNA-C2, SAAVI MVA-C and Novartis gp140 with MF59 adjuvant in various combinations were safe and induced neutralizing and binding antibodies and cellular immune responses. Sequential immunization with gp140 boosted immune responses primed by MVA or DNA. The best overall immune responses were seen with the M/M/P/P regimen. Trial Registration ClinicalTrials.gov NCT01418235