Common Features of Mucosal and Peripheral Antibody Responses Elicited by Candidate HIV-1 Vaccines in Rhesus Monkeys

Abstract

bHuman immunodeficiency virus type 1 (HIV-1) vaccines that elicit protective antibody responses at mucosal sites would be highly desirable. Here, we report that intramuscular immunization of candidate HIV-1 vaccine vectors and purified Env proteins elicited potent and durable humoral immune responses in colorectal mucosa in rhesus monkeys. The kinetics, isotypes, functionality, and epitope specificity of these mucosal antibody responses were similar to those of peripheral responses in serum. These data suggest a close immunological relationship between mucosal and systemic antibody responses following vaccination in primates. Human mucosal surfaces represent the major portal of entry for human immunodeficiency virus type 1 (HIV-1) (1). Thus, a prophylactic vaccine will likely need to elicit protective antibody responses at mucosal sites of virus exposure. However, mucosal humoral immune responses following vaccination are poorly characterized. The RV144 clinical trial suggested that vaccine-elicited HIV-1 envelope (Env)-specific humoral immune responses may have contributed to the partial protection observed for vaccinees (2), but mucosal immune responses were not assessed in that trial. In contrast, previous studies have shown that immunization with peptide, DNA, protein, or attenuated bacterial or viral vector-based vaccines through parental or mucosal routes may elicit antigen-specific humoral immune responses at mucosal sites in mice, nonhuman primates, and humans (3-7). However, the characteristics, functionality, and epitope specificity of vaccine-elicited mucosal antibody responses have not been fully explored. Moreover, whether mucosal antibody responses reflect distinct populations compared with those for peripheral antibody responses remains to be determined. We therefore assessed the magnitude, durability, isotype, neutralizing activity, and epitope specificity of mucosal and peripheral antibody responses in rhesus monkeys elicited by adenovirus (Ad) vector-based and proteinbased HIV-1 vaccine candidates.We first collected blood and colorectal mucosal secretions using Weck-Cel sponges from 8 healthy adult rhesus monkeys. Using sera and mucosal secretions eluted from Weck-Cel sponges (8), we assessed the amount of total IgG and IgA (monkey IgG/IgA enzyme-linked immunosorbent assay [ELISA] kit; Alpha Diagnostic). The average volume of eluates from 8 unused sponges was used as the elution buffer volume, and a dilution factor was calculated according to the volume of eluate for each sample: dilution factor ϭ experiment sponge eluate volume/(experiment sponge eluate volume Ϫ unused sponge eluate volume). The dilution factor was used to calculate total IgG and IgA as well as titers

Similar Epitope Specificities of IgG and IgA Antibodies Elicited by Ad26 Vector Prime, Env Protein Boost Immunizations in Rhesus Monkeys

“…To assess Env-specific binding antibody titers from serum and colorectal secretions, we assessed samples from 4 weeks after each Env immunization (weeks 28, 53, 80) by ELISA. Consistent with our previous observations ( 14 ), Env-specific IgG and IgA responses were elicited in both the serum and mucosal compartments, and the kinetics of the mucosal antibody titers closely mimicked those in serum ( Fig. 1A and B ).…”

“…1 and 2A ). These data suggest that systemic and mucosal antibody responses are immunologically coordinated, with mucosal antibodies likely reflecting transudation of serum antibodies into mucosal compartments ( 14 , 29 , 30 ). These findings confirm and extend prior studies.…”

Virus-Like Particles Displaying Trimeric Simian Immunodeficiency Virus (SIV) Envelope gp160 Enhance the Breadth of DNA/Modified Vaccinia Virus Ankara SIV Vaccine-Induced Antibody Responses in Rhesus Macaques

“…4B). As expected, Env-specific mucosal IgG responses strongly correlated with systemic IgG responses (P Ͻ 0.01) (data not shown) (32). Similarly to the responses in sera, we found a significant increase in anti-Gag IgG titers in the rectal mucosa.…”

Biophysical and Functional Characterization of Rhesus Macaque IgG Subclasses

“…Though previous studies have aimed to characterize the induction of specific IgG subclasses among vaccinated rhesus macaques (61, 62), collectively, the findings in this study suggest that the functional differences associated with subclass-switching profiles observed in human HIV vaccines cannot be strictly recapitulated in NHP vaccine studies. Accordingly, care must be taken not to presume the significance of “nominal” correspondence of subclass types.…”