Vaccine Inoculation Route Modulates Early Immunity and Consequently Antigen-Specific Immune Response

Abstract

Vaccination is one of the most efficient public healthcare measures to fight infectious diseases. Nevertheless, the immune mechanisms induced in vivo by vaccination are still unclear. The route of administration, an important vaccination parameter, can substantially modify the quality of the response. How the route of administration affects the generation and profile of immune responses is of major interest. Here, we aimed to extensively characterize the profiles of the innate and adaptive response to vaccination induced after intradermal, subcutaneous, or intramuscular administration with a modified vaccinia virus Ankara model vaccine in non-human primates. The adaptive response following subcutaneous immunization was clearly different from that following intradermal or intramuscular immunization. The subcutaneous route induced a higher level of neutralizing antibodies than the intradermal and intramuscular vaccination routes. In contrast, polyfunctional CD8+ T-cell responses were preferentially induced after intradermal or intramuscular injection. We observed the same dichotomy when analyzing the early molecular and cellular immune events, highlighting the recruitment of cell populations, such as CD8+ T lymphocytes and myeloid-derived suppressive cells, and the activation of key immunomodulatory gene pathways. These results demonstrate that the quality of the vaccine response induced by an attenuated vaccine is shaped by early and subtle modifications of the innate immune response. In this immunization context, the route of administration must be tailored to the desired type of protective immune response. This will be achieved through systems vaccinology and mathematical modeling, which will be critical for predicting the efficacy of the vaccination route for personalized medicine.

The route of vaccine administration determines whether blood neutrophils undergo long-term phenotypic modifications

“…Most importantly, it involved a similar distribution of cell subsets, in contrast to the response to a second SC injection, which engaged more highly mature/activated cells that were induced long after the first administration of the vaccine (9). Thus, depending on the route of MVA administration, not only the Ab and T cells responses (8), and the early inflammatory/innate responses to the first immunization (Figures 2B, 3 and 5C, and as previously shown (8,9)) differed, but also the long-term impact on neutrophils (Figure 5C and as previously shown ( 9)).…”

“…Animals were immunized twice, two months apart, with the ANRS recombinant MVA-HIV B vaccine (Transgene) at a dose of 4 x 10e 8 plaque forming units (PFU) by ID injections distributed over 10 injection points (150 μL/point of injections, all along the back, in two columns). Recombinant HIV-1 antigens consisted of the complete sequence of gag, fused to fragments from pol (residues 172-219, 325-383 and 461-519) and nef (residues 66-147 and 182-206) of the Bru/Lai isolate.…”

“…The route of vaccine administration influences antigen/adjuvant trafficking, local and systemic inflammation, innate effectors, and the resulting adaptive immune response (4)(5)(6)(7). We have shown that, like the antigen-specific antibody and T-cell responses, the early innate responses differ between subcutaneous (SC) and intradermal (ID) immunization, with the recruitment of distinct cell populations and activation of different immunomodulatory genes in skin and blood in response to a model live attenuated vaccine, Modified vaccinia virus Ankara (MVA), in non-human primates (NHPs) (8).…”

The Route of Vaccine Administration Determines Whether Blood Neutrophils Undergo Long-Term Phenotypic Modifications

“…We assessed the humoral response to confirm the efficiency of vaccination, as Abs are the main immune correlate of protection for most vaccines (16), including vaccinia virus (VACV) and MVA against smallpox (17). As previously shown (8), MVA was highly immunogenic after ID injection. It induced high levels of MVA-specific IgGs (Figure 1B).…”

“…The route of vaccine administration influences antigen/ adjuvant trafficking, local and systemic inflammation, innate effectors, and the resulting adaptive immune response (4)(5)(6)(7). We have shown that, like the antigen-specific antibody and Tcell responses, the early innate responses differ between subcutaneous (SC) and intradermal (ID) immunization, with the recruitment of distinct cell populations and activation of different immunomodulatory genes in skin and blood in response to a model live attenuated vaccine, Modified vaccinia virus Ankara (MVA), in non-human primates (NHPs) (8).…”