Posted in HIV, Resource

Molecular Signatures of a TLR4 Agonist-Adjuvanted HIV-1 Vaccine Candidate in Humans

Molecular signatures associated with early (A) and late (B) humoral responses. Source from Anderson et al., 2018, Frontiers in Immunology

Immunisation with the stable trimeric recombinant HIV-1 envelope glycoprotein, CN54gp140, has been shown to induce potent humoral immune responses, especially when adjuvanted with TLR4 agonist adjuvants, such as monophosphoryl lipid A or GLA-AF (glucopyranosol lipid adjuvant-aqueous formulation). These adjuvants exert their adjuvanticity, at least in part, by activating the myeloid differentiation factor 88 (MyD88) and toll-interleukin 1 receptor domain-containing adapter inducing interferon-β (TRIF) pathways. However, the clinical efficacy to the CN54gp140 adjuvanted with GLA-AF is variable between individuals. Anderson et al characterised the host responses after vaccinating subjects with CN54gp140 adjuvanted with GLA-AF, and examined the gene signatures linked to vaccine immunogenicity. 

Healthy male (n = 8) or female (n = 6) volunteers aged between 18 and 45 and with no history of HIV-1 and HIV-2 infection received the vaccine, and whole blood was collected from these subjects at 6 hours, 1, 3 and 7 days after vaccination. 

Majority of total DEGs were observed within 24 h post vaccination compared to later time points at 3 days and 7 days post-immunisation. 

The DEGs reveal an enrichment of BTMs related to cell cycle regulation and signaling as well as those related to innate and adaptive immune responses.

NK cell-related enriched BTMs (M7.2, M61.0, and S1) were significantly repressed in the gene expression profiles from individuals with either late high serum IgA or IgG4 responders (See Figure on top). 

In particular, we identified a repression in BTM modules related to NK cells, especially at 3 and 7 days post-vaccination, for high serum IgM, IgA, and IgG4 antibody responders.

Flow cytometry was performed to determine that the changes were due to NK cell numbers or expression levels of proteins upon vaccination.

In the limited number of analyzed samples, frequency of CD3–CD56dim NK cell population in the blood of high antibody responder subjects was increased on 14 days post vaccination compared to the 0 h baseline. While more studies need to be done, the authors speculate that the repression of BTMs related to NK cells observed in the first 7 days post-vaccination reflects NK cells leaving the circulation early in the response. Given that NK cells are short lived, the enhanced frequency of NK cells for 14  days post vaccination is presumably attributed to secondary induction of NK cell differentiation processes in response to vaccination.