background/introduction methodology conclusions limitations results
Predictors of HVTN 503 MRK AD5 HIV-1 gag/pol/nef vaccine-induced immune response Kate Cerwensky1, Fatima Laher1, Kennedy Otwombe1, Gavin Churchyard2, Linda-Gail Bekker3, Maphoshane Nchabeleng4, Koleka Mlisana⁵, Jim Kublin⁶, Glenda Gray1 Author affiliations: 1Perinatal HIV Research Unit, University of Witwatersrand, South Africa; 2Aurum Institute for Health Research, School of Public Health, University of Witwatersrand, South Africa; 3Desmond Tutu HIV Centre, University of Cape Town, South Africa; 4Medunsa HIV Clinical Research Unit, University of Limpopo, South Africa; ⁵Centre for AIDS Programme for Research in South Africa & Department of Medical Microbiology, University of KZN, South Africa; Clade C Univariate Clade C Multivariate Fred Hutchinson Cancer Research Center, Seattle, WA, USA Corresponding Author: Kate Cerwensky, [email protected]
BACKGROUND/INTRODUCTION
Phambili (HVTN 503) was a Phase IIb HIV vaccine efficacy study conducted in South Africa. It investigated the Merck (MRK) Adenovirus type-5 (Ad5) HIV-1 clade B trivalent HIV vaccine, containing recombinant Ad5 vectors expressing clade B gag, pol, and nef epitopes. The trial suspended enrolment and vaccination when its companion study, Step (HVTN 502/Merck 023), was found futile. Although the vaccine neither prevented HIV-1 infection nor lowered viral load setpoint, immune responses recognizing clades B and C HIV-1 subtypes were elicited. There is scarce data revealing the innate predictors – such as age or obesity - affecting immune responses and how this could affect vaccine efficacy. It is not yet known if there are influential factors on the Phambili vaccine-induced immune response. We investigate predictors associated with the MRK-Ad5 vaccine-specific T-cell immune response for HIV-1 clade B and clade C amongst South African participants in an attempt to further improve upon future HIV vaccine candidates.
METHODOLOGY
Study Design: Multicentre, double-blind, randomized, placebocontrolled clinical trial conducted 24 January - 19 September, 2007, at five sites: Soweto, Cape Town, Klerksdorp, eThekwini, and Medunsa. Eligibility: Consenting, healthy, HIV-1-uninfected men and women (18-35 yrs); sexually active within six months of enrolment. Women could not be pregnant or breastfeeding and had to agree to use two methods of contraception. Procedures: Blocked randomization (for sites, gender) 1:1 between vaccine and placebo. Vaccines or placebo injected intramuscularly at 0, 1, 6 months. Neutralising Ad5 antibody titre levels and herpes simplex type-2 were determined at enrolment via serum samples. Heavy drinking was reported six months prior to enrolment. Immunological Testing: Vaccine immunogenicity was assessed by interferon-γ ELISPOT assays on the first 186 enrolled vaccine and placebo recipients, four weeks after the second vaccination
Statistical Analysis: Descriptive and frequency analysis, stratified by study arm and gender, were performed on baseline demographics (gender, age, BMI, study site, Ad5 titre, HSV2 status, and heavy drinking). Univariate and multivariate logistic regression determined predictors of immune response to both any and cladespecific antigens in the 93 vaccine-recipients. Backward selection technique was performed for multivariate variable selection, and analyses were two-sided with 5% level of significance. (SAS 9•3).
RESULTS
*BMI: underweight (< 18•5), normal (18•5-24•9), overweight (25•029•9), and obese (>29•9). †Ad5 titre: positive (> 18 units) and negative (≤ 18 units). ‡Heavy drinking: more than five drinks per day on at least ten days within six months of the screening and enrolment period. Variable
Vaccine Arm (n=93) Placebo Arm (n=93) Males Females Males Females (n=42, 45%) (n=51, 55%) (n=44, 47%) (n=49, 53%) Study Site (n, %) Soweto 22 (52•4) 29 (56•9) 20 (45•5) 29 (59•2) KOSH 12 (28•6) 7 (13•7) 16 (36•4) 6 (12•2) Cape Town 8 (19•0) 15 (29•4) 8 (18•2) 14 (28•6) Median Age in years (IQR) 23 (21-27) 23 (20-27) 23 (21-27) 24 (21-28) Median BMI (IQR) 20•9 25•0 20•9 25•5 (18•8-22•3) (21•6-29•7) (19•7-23•2) (22•2-30•4) Median BMI by site (IQR) 20•3 23•6 20•7 25•2 Soweto (18•3-21•0) (21•3-26•7) (19•8-22•8) (22•5-28•6) 21•2 21•4 19•9 20•9 KOSH (19•2-22•2) (17•0-27•4) (19•3-21•0) (18•1-25•5) 23•0 29•5 28•6 31•6 Cape Town (22•3-24•7) (26•6-31•6) (22•9-31•2) (25•1-42•0) Ad5 Titre (%) 1000 8 (19•0) 8 (15•7) 6 (13•6) 11 (22•4) HSV-2 Status (%) Positive 11 (26•2) 31 (60•8) 6 (13•6) 26 (53•1) Negative 31 (73•8) 20 (39•2) 36 (81•8) 23 (46•9) Atypical 0 (0) 0 (0) 2 (4•5) 0 (0) Heavy Drinking (%) Yes 15 (35•7) 3 (5•9) 12 (27•3) 5 (10•2) No 27 (64•3) 48 (94•1) 32 (72•7) 44 (89•8) Table 1: Baseline Characteristics at Enrolment
Total (N=186) 100 (53•8) 41 (22•0) 45 (24•2) 23 (21-27) 22•5 (20•4-27•0) 22•0 (20•2-25•3) 20•7 (19•1-22•1) 28•0 (23•3-32•4)
27 (14•5) 52 (28•0) 74 (39•8) 33 (17•7) 74 (39•8) 110 (59•1) 2 (1•1) 35 (18•8) 151 (81•2)
OR (95% CI)
p-value
OR (95% CI)
p-value
Gender: Male - Reference 3•143 6•478 Female (1•129-8•747) 0•028 (1•419-29•570) Study Site: Others - Reference 0•529 0•310 Soweto (0•191-1•463) 0•220 (0•090-1•069) Age Group: ≤ 24 years - Reference 1•349 > 24 years (0•485-3•749) 0•566 1•074 (0•335-3•443) BMI: Overweight/Obese - Reference 0•972 5•365 Normal/Underfv (0•332-2•845) 0•958 (1•036-27•770) Ad5 Titre: Negative - Reference 0•633 0•349 Positive (0•164-2•438) 0•507 (0•076-1•602) Heavy Drinking: No - Reference 0•262 0•270 Yes (0•087-0•792) 0•018 (0•073-0•990) Table 2: Predictors of Phambili Vaccine Immune Response for any Clade C Antigens
0•016
0•064
CONCLUSIONS All 93 vaccine-recipients showed immune responses to either clade B and/or clade C antigens; however, consistent with the regional clade prevalence, there were only significant predictors of an immunologic response to clade C.
0•904
0•045
0•176
0•048
Our study demonstrates that female gender or normal/underweight BMI significantly boosts immune response to any clade C antigen. Heavy drinking significantly inhibits the same immune response. Specifically, female gender is marginally significant in boosting immune response to the clade C-pol antigen. Baseline NAd5 titre levels were not a statistically significant predictor of vaccine immune response. Stratification by gender and BMI should be considered in future vaccine efficacy trials to assess the effects on HIV-1 vaccines by these predictors.
LIMITATIONS The premature halt of Phambili, may have potentially affected the detection of additional predictors and/or stronger associations.
BACKGROUND/INTRODUCTION
Phambili (HVTN 503) was a Phase IIb HIV vaccine efficacy study conducted in South Africa. It investigated the Merck (MRK) Adenovirus type-5 (Ad5) HIV-1 clade B trivalent HIV vaccine, containing recombinant Ad5 vectors expressing clade B gag, pol, and nef epitopes. The trial suspended enrolment and vaccination when its companion study, Step (HVTN 502/Merck 023), was found futile. Although the vaccine neither prevented HIV-1 infection nor lowered viral load setpoint, immune responses recognizing clades B and C HIV-1 subtypes were elicited. There is scarce data revealing the innate predictors – such as age or obesity - affecting immune responses and how this could affect vaccine efficacy. It is not yet known if there are influential factors on the Phambili vaccine-induced immune response. We investigate predictors associated with the MRK-Ad5 vaccine-specific T-cell immune response for HIV-1 clade B and clade C amongst South African participants in an attempt to further improve upon future HIV vaccine candidates.
METHODOLOGY
Study Design: Multicentre, double-blind, randomized, placebocontrolled clinical trial conducted 24 January - 19 September, 2007, at five sites: Soweto, Cape Town, Klerksdorp, eThekwini, and Medunsa. Eligibility: Consenting, healthy, HIV-1-uninfected men and women (18-35 yrs); sexually active within six months of enrolment. Women could not be pregnant or breastfeeding and had to agree to use two methods of contraception. Procedures: Blocked randomization (for sites, gender) 1:1 between vaccine and placebo. Vaccines or placebo injected intramuscularly at 0, 1, 6 months. Neutralising Ad5 antibody titre levels and herpes simplex type-2 were determined at enrolment via serum samples. Heavy drinking was reported six months prior to enrolment. Immunological Testing: Vaccine immunogenicity was assessed by interferon-γ ELISPOT assays on the first 186 enrolled vaccine and placebo recipients, four weeks after the second vaccination
Statistical Analysis: Descriptive and frequency analysis, stratified by study arm and gender, were performed on baseline demographics (gender, age, BMI, study site, Ad5 titre, HSV2 status, and heavy drinking). Univariate and multivariate logistic regression determined predictors of immune response to both any and cladespecific antigens in the 93 vaccine-recipients. Backward selection technique was performed for multivariate variable selection, and analyses were two-sided with 5% level of significance. (SAS 9•3).
RESULTS
*BMI: underweight (< 18•5), normal (18•5-24•9), overweight (25•029•9), and obese (>29•9). †Ad5 titre: positive (> 18 units) and negative (≤ 18 units). ‡Heavy drinking: more than five drinks per day on at least ten days within six months of the screening and enrolment period. Variable
Vaccine Arm (n=93) Placebo Arm (n=93) Males Females Males Females (n=42, 45%) (n=51, 55%) (n=44, 47%) (n=49, 53%) Study Site (n, %) Soweto 22 (52•4) 29 (56•9) 20 (45•5) 29 (59•2) KOSH 12 (28•6) 7 (13•7) 16 (36•4) 6 (12•2) Cape Town 8 (19•0) 15 (29•4) 8 (18•2) 14 (28•6) Median Age in years (IQR) 23 (21-27) 23 (20-27) 23 (21-27) 24 (21-28) Median BMI (IQR) 20•9 25•0 20•9 25•5 (18•8-22•3) (21•6-29•7) (19•7-23•2) (22•2-30•4) Median BMI by site (IQR) 20•3 23•6 20•7 25•2 Soweto (18•3-21•0) (21•3-26•7) (19•8-22•8) (22•5-28•6) 21•2 21•4 19•9 20•9 KOSH (19•2-22•2) (17•0-27•4) (19•3-21•0) (18•1-25•5) 23•0 29•5 28•6 31•6 Cape Town (22•3-24•7) (26•6-31•6) (22•9-31•2) (25•1-42•0) Ad5 Titre (%) 1000 8 (19•0) 8 (15•7) 6 (13•6) 11 (22•4) HSV-2 Status (%) Positive 11 (26•2) 31 (60•8) 6 (13•6) 26 (53•1) Negative 31 (73•8) 20 (39•2) 36 (81•8) 23 (46•9) Atypical 0 (0) 0 (0) 2 (4•5) 0 (0) Heavy Drinking (%) Yes 15 (35•7) 3 (5•9) 12 (27•3) 5 (10•2) No 27 (64•3) 48 (94•1) 32 (72•7) 44 (89•8) Table 1: Baseline Characteristics at Enrolment
Total (N=186) 100 (53•8) 41 (22•0) 45 (24•2) 23 (21-27) 22•5 (20•4-27•0) 22•0 (20•2-25•3) 20•7 (19•1-22•1) 28•0 (23•3-32•4)
27 (14•5) 52 (28•0) 74 (39•8) 33 (17•7) 74 (39•8) 110 (59•1) 2 (1•1) 35 (18•8) 151 (81•2)
OR (95% CI)
p-value
OR (95% CI)
p-value
Gender: Male - Reference 3•143 6•478 Female (1•129-8•747) 0•028 (1•419-29•570) Study Site: Others - Reference 0•529 0•310 Soweto (0•191-1•463) 0•220 (0•090-1•069) Age Group: ≤ 24 years - Reference 1•349 > 24 years (0•485-3•749) 0•566 1•074 (0•335-3•443) BMI: Overweight/Obese - Reference 0•972 5•365 Normal/Underfv (0•332-2•845) 0•958 (1•036-27•770) Ad5 Titre: Negative - Reference 0•633 0•349 Positive (0•164-2•438) 0•507 (0•076-1•602) Heavy Drinking: No - Reference 0•262 0•270 Yes (0•087-0•792) 0•018 (0•073-0•990) Table 2: Predictors of Phambili Vaccine Immune Response for any Clade C Antigens
0•016
0•064
CONCLUSIONS All 93 vaccine-recipients showed immune responses to either clade B and/or clade C antigens; however, consistent with the regional clade prevalence, there were only significant predictors of an immunologic response to clade C.
0•904
0•045
0•176
0•048
Our study demonstrates that female gender or normal/underweight BMI significantly boosts immune response to any clade C antigen. Heavy drinking significantly inhibits the same immune response. Specifically, female gender is marginally significant in boosting immune response to the clade C-pol antigen. Baseline NAd5 titre levels were not a statistically significant predictor of vaccine immune response. Stratification by gender and BMI should be considered in future vaccine efficacy trials to assess the effects on HIV-1 vaccines by these predictors.
LIMITATIONS The premature halt of Phambili, may have potentially affected the detection of additional predictors and/or stronger associations.
