Divergent HIV-1-Directed Immune Responses Generated by Systemic and Mucosal Immunization with Replicating Single-Cycle Adenoviruses in Rhesus Macaques

Abstract

Most human immunodeficiency virus type 1 (HIV-1) infections begin at mucosal surfaces. Providing a barrier of protection at these may assist in combating the earliest events in infection. Systemic immunization by intramuscular (i.m.) injection can drive mucosal immune responses, but there are data suggesting that mucosal immunization can better educate these mucosal immune responses. To test this, rhesus macaques were immunized with replicating single-cycle adenovirus (SC-Ad) vaccines expressing clade B HIV-1 gp160 by the intranasal (i.n.) and i.m. routes to compare mucosal and systemic routes of vaccination. SC-Ad vaccines generated significant circulating antibody titers against Env after a single i.m. immunization. Switching the route of second immunization with the same SC-Ad serotype allowed a significant boost in these antibody levels. When these animals were boosted with envelope protein, envelope-binding antibodies were amplified 100-fold, but qualitatively different immune responses were generated. Animals immunized by only the i.m. route had high peripheral T follicular helper (pTfh) cell counts in blood but low Tfh cell counts in lymph nodes. Conversely, animals immunized by the i.n. route had high Tfh cell counts in lymph nodes but low pTfh cell counts in the blood. Animals immunized by only the i.m. route had lower antibody-dependent cellular cytotoxicity (ADCC) antibody activity, whereas animals immunized by the mucosal i.n. route had higher ADCC antibody activity. When these Env-immunized animals were challenged rectally with simian-human immunodeficiency virus (SHIV) strain SF162P3 (SHIVSF162P3), they all became infected. However, mucosally SC-Ad-immunized animals had lower viral loads in their gastrointestinal tracts. These data suggest that there may be benefits in educating the immune system at mucosal sites during HIV vaccination. IMPORTANCE HIV-1 infections usually start at a mucosal surface after sexual contact. Creating a barrier of protection at these mucosal sites may be a good strategy for to protect against HIV-1 infections. While HIV-1 enters at mucosa, most vaccines are not delivered here. Most are instead injected into the muscle, a site well distant and functionally different than mucosal tissues. This study tested if delivering HIV vaccines at mucosa or in the muscle makes a difference in the quality, quantity, and location of immune responses against the virus. These data suggest that there are indeed advantages to educating the immune system at mucosal sites with an HIV-1 vaccine.

Genetic Adjuvants in Replicating Single-Cycle Adenovirus Vectors Amplify Systemic and Mucosal Immune Responses against HIV-1 Envelope

“…These protein boosts increased midpoint binding titers by two orders of magnitude in all of the groups. Interestingly, the IN-IN-IN group, which had no antibodies at week 24, boosted as strongly as the other groups [43]. These immunizations generated significant cellular responses and antibody-dependent cellular cytotoxicity (ADCC) activity and clade B HIV neutralizing antibodies [43].…”

“…Animals that were immunized predominantly by the mucosal route had env-binding antibodies in their saliva near the site of immunization. However, only a few of these animals had antibodies at the more distant vaginal site [43].…”

“…SC-Ads generate antibodies and T cells responses that increase over 12 months after single immunization vs. HIV, influenza, Ebola, Zika, or C. difficile antigens [38,[41][42][43][44][45][46][47][48]. SC-Ad carrying influenza hemagglutinin (HA) produced markedly more antigen than RD-Ad in vitro, requiring 33- While RC-Ads are documented to be more potent than RD-Ad vectors, replication-competent Ads pose a real risk of causing adenovirus infections as a side-effect of vaccination.…”

“…SC-Ad serotype 6 vectors expressing HIV clade B envelope sequences were used to vaccinate rhesus macaques by the IN or IM [43]. Single immunization by the IM route generated significant envelope antibodies within four weeks.…”

Intramuscular Immunization with Chemokine-Adjuvanted Inactive Porcine Epidemic Diarrhea Virus Induces Substantial Protection in Pigs

“…Many attempts have been made to develop a safe and protective vaccine for controlling PED [4][5][6][7][8][9][10]. However, similar to studies on most enterotropic and mucosal transmissible viral diseases [11][12][13][14], using intramuscular (IM) administration of inactive or subunit vaccines combined with commercial adjuvants, such as multiple emulsions of water/oil/water or a B subunit of Escherichia coli heat-labile enterotoxin (LTB) induced production of systemic IgG and neutralizing antibodies but failed to elicit a mucosal IgA response and efficient protection [6,7,[15][16][17]. Furthermore, poor efficacies of currently commercialized vaccines have been reported [18][19][20].…”