Mucosal B Cells Are Associated with Delayed SIV Acquisition in Vaccinated Female but Not Male Rhesus Macaques Following SIVmac251 Rectal Challenge.
Many viral infections, including HIV, exhibit sex-based pathogenic differences. However, few studies have examined vaccine-related sex differences. We compared immunogenicity and protective efficacy of monomeric SIV gp120 with oligomeric SIV gp140 in a pre-clinical rhesus macaque study and explored a subsequent sex bias in vaccine outcome. Each immunization group (16 females, 8 males) was primed twice mucosally with replication-competent Ad-recombinants encoding SIVsmH4env/rev, SIV239gag and SIV239nefΔ1-13 and boosted twice intramuscularly with SIVmac239 monomeric gp120 or oligomeric gp140 in MF59 adjuvant. Controls (7 females, 5 males) received empty Ad and MF59. Up to 9 weekly intrarectal challenges with low-dose SIVmac251 were administered until macaques became infected. We assessed vaccine-induced binding, neutralizing, and non-neutralizing antibodies, Env-specific memory B cells and plasmablasts/plasma cells (PB/PC) in bone marrow and rectal tissue, mucosal Env-specific antibodies, and Env-specific T-cells. Post-challenge, only one macaque (gp140-immunized) remained uninfected. However, SIV acquisition was significantly delayed in vaccinated females but not males, correlated with Env-specific IgA in rectal secretions, rectal Env-specific memory B cells, and PC in rectal tissue. These results extend previous correlations of mucosal antibodies and memory B cells with protective efficacy. The gp140 regimen was more immunogenic, stimulating elevated gp140 and cyclic V2 binding antibodies, ADCC and ADCP activities, bone marrow Env-specific PB/PC, and rectal gp140-specific IgG. However, immunization with gp120, the form of envelope immunogen used in RV144, the only vaccine trial to show some efficacy, provided more significant acquisition delay. Further over 40 weeks of follow-up, no gp120 immunized macaques met euthanasia criteria in contrast to 7 gp140-immunized and 2 control animals. Although males had higher binding antibodies than females, ADCC and ADCP activities were similar. The complex challenge outcomes may reflect differences in IgG subtypes, Fc glycosylation, Fc-R polymorphisms, and/or the microbiome, key areas for future studies. This first demonstration of a sex-difference in SIV vaccine-induced protection emphasizes the need for sex-balancing in vaccine trials. Our results highlight the importance of mucosal immunity and memory B cells at the SIV exposure site for protection.
Immune Biology of Retroviral Infection Section, Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Iskra
I
Tuero
Immune Biology of Retroviral Infection Section, Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Venkatramanan
V
Mohanram
Immune Biology of Retroviral Infection Section, Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Thomas
T
Musich
Immune Biology of Retroviral Infection Section, Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Leia
L
Miller
Immune Biology of Retroviral Infection Section, Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Diego A
DA
Vargas-Inchaustegui
Immune Biology of Retroviral Infection Section, Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Thorsten
T
Demberg
Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
David
D
Venzon
Advanced Bioscience Laboratories, Inc., Rockville, Maryland, United States of America.
Irene
I
Kalisz
Advanced Bioscience Laboratories, Inc., Rockville, Maryland, United States of America.
V S
VS
Kalyanaraman
Advanced Bioscience Laboratories, Inc., Rockville, Maryland, United States of America.
Ranajit
R
Pal
Advanced Bioscience Laboratories, Inc., Rockville, Maryland, United States of America.
Maria Grazia
MG
Ferrari
Duke University Medical Center, Durham, North Carolina, United States of America.
Celia
C
LaBranche
Duke University Medical Center, Durham, North Carolina, United States of America.
David C
DC
Montefiori
USMHRP, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
Mangala
M
Rao
Animal Models and Retroviral Vaccines Section, Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Monica
M
Vaccari
Animal Models and Retroviral Vaccines Section, Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Genoveffa
G
Franchini
Novartis Vaccines, Cambridge, Massachusetts, United States of America.
Susan W
SW
Barnett
Immune Biology of Retroviral Infection Section, Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Marjorie
M
Robert-Guroff
D000818:Animals; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D005260:Female; D007111:Immunity, Cellular / Q000276:immunology; D018928:Immunity, Mucosal / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology*; D008253:Macaca mulatta; D008297:Male; D012007:Rectum; D018449:SAIDS Vaccines / Q000276:immunology*; D012737:Sex Factors; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000517:prevention & control; D015302:Simian Immunodeficiency Virus / Q000276:immunology
D000914:Antibodies, Viral; D018449:SAIDS Vaccines