TCR-contacting residues orientation and HLA-DRβ* binding preference determine long-lasting protective immunity against malaria

Specific β-Turns Precede PPIIL Structures Binding to Allele-Specific HLA-DRβ1* PBRs in Fully-Protective Malaria Vaccine Components

“…This was the first demonstration that chemically-synthesized, vaccine-induced immune protection was associated with a particular 3D structure; (Patarroyo et al, 2015a ). As the ideal one should specifically bind to HLA-DRβ1 * alleles, it was called Group A, inducing LLPI and having 26.5 ± 1.5 Å distance between residues 1 to 9 fitting into HLA-DRβ1 * PBR (Alba et al, 2016 ), all having or containing PPII L -like structures. This confirmed that PPII L -like conformation is an absolute requirement for LLPI induction.…”

“…This confirmed that PPII L -like conformation is an absolute requirement for LLPI induction. Group B induced s hort-lived p rotective i mmunity (SPI) whose structure in the PBR binding region (HLA-DR residues 1 to 9) was ~3.5Å shorter, preferentially binding to HLA-DRβ3 * , β4 * or β5 * haplotypes (Alba et al, 2016 ). Group C consisted of n on- p rotective a ntibody- i nducing (NPAI) mHABPs which were shorter in the PBR binding region and group D consisted of native cHABPs which did not induce antibody production or protection (Figure 1 ) or binding to any Class II molecule when used as immunogens, according to the netMHCIIpan 3.1. platform (Andreatta et al, 2015 ) (Figure 2 ).…”

“…This observation prompted us to look for an association between such immunological functions and particular 3D structures, applying Francis Cricks catch-phrase, “If you do not understand function, study structure and vice versa.” After having obtained ~300 3D structures for these peptides by powerful 1 H-NMR spectroscopic analysis (600 MHz), we searched for an association between these characteristics and particular 3D structure conformation in our peptides (Patarroyo et al, 2011 , 2012a , b , 2015a , b ; Bermúdez et al, 2014 ; Alba et al, 2016 ; Reyes et al, 2017a ).…”

“…LLPI-IMPIPS was assessed by re-challenging Aotus monkeys having high antibody titres and positive protection (defined as the complete absence of the parasite in a monkey's blood stream) 60 days after the end of the first trial in which a monkey proved fully-protected (Bermúdez et al, 2014 ; Alba et al, 2016 ).…”

“…This manuscript is aimed at showing that, in the search for l ong- l asting, p rotective i mmunity (LLPI), these PPII L -like structures must be preceded by specific and particular β-turn structures which, when preceding other structures like α R -helixes and/ or other β-turn types, could also activate immune system molecules whilst inducing s hort-lived p rotective i mmunity (SPI) structures. When associated with PPII L amino acid sequences binding to the HLA-DRβ1 * PBR having appropriate TCR contacting residue orientation, modified high activity binding peptides (mHABPs) can induce LLPI, which we have named IMPIPS (Patarroyo et al, 2015a ; Alba et al, 2016 ). Specific preference for some of these β-turns and the complete absence of some others is also shown, as is the preferred association between some residues in both β-turns and PPII L PBR sequences leading to high antibody titres and LLPI induction.…”