Biology subjects

Crotty, S.

Publications and source records attributed to Crotty, S..

39 records · Page 3Linked to original sources

bioRxiv2018

Vaccine-induced protection from homologous Tier 2 simian-human immunodeficiency virus challenge in nonhuman primates

Passive administration of HIV neutralizing antibodies (nAbs) can protect macaques from hard-to-neutralize (Tier 2) chimeric simian-human immunodeficiency virus (SHIV) challenge. However, conditions for nAb-mediated protection following vaccination have not been established. Here, we selected groups of 6 rhesus macaques with either high or low serum nAb titers from a total of 78 animals immunized with recombinant native-like (SOSIP) Env trimers from the BG505 HIV isolate. Repeat intrarectal challenge with homologous Tier 2 SHIVBG505 led to rapid infection in unimmunized and low-titer animals. In contrast, high-titer animals demonstrated protection that was gradually lost as nAb titers waned over weeks to months. From these results, we determined that an autologous serum ID50 nAb titer of ~1:500 was required to afford over 90% protection from medium-dose SHIV infection. We further identified autologous nAb titers, but not ADCC or T cell activity, as strong correlates of protection. These results provide proof-of-concept that Env protein-based vaccination strategies can protect against hard-to-neutralize SHIV challenge in rhesus macaques by inducing Tier 2 nAbs, provided appropriate neutralizing titers can be reached and maintained.

immunology↗

bioRxiv2018

Slow delivery immunization enhances HIV neutralizing antibody and germinal center responses via modulation of immunodominance

The observation that humans can produce broadly neutralizing antibodies (bnAbs) against HIV-1 has generated enthusiasm about the potential for a bnAb vaccine against HIV-1. Conventional immunization strategies will likely be insufficient for the development of a bnAb HIV vaccine and vaccines to other difficult pathogens, due to the significant immunological hurdles posed, including B cell immunodominance and germinal center (GC) quantity and quality. Using longitudinal lymph node fine needle aspirates, we found that two independent methods of slow delivery immunization of rhesus macaques (RM) resulted in larger GCs, more robust and sustained GC Tfh cell responses, and GC B cells with improved Env-binding, which correlated with the development of ~20 to 30-fold higher titers of tier 2 HIV-1 nAbs. Using a new RM genomic immunoglobulin loci reference sequence, we identified differential IgV gene usage between slow delivery immunized and conventional bolus immunized animals. The most immunodominant IgV gene used by conventionally immunized animals was associated with many GC B cell lineages. Ab mapping of those GC B cell specificities demonstrated targeting of an immunodominant non-neutralizing trimer base epitope, while that response was muted in slow delivery immunized animals. Thus, alternative immunization strategies appear to enhance nAb development by altering GCs and modulating immunodominance of non-neutralizing epitopes.

immunology↗

bioRxiv2018

Evidence that recurrent Group A streptococcus tonsillitis is animmunosusceptibility disease involving antibody deficiency and aberrant Tfh cells

One Sentence SummaryRecurrent tonsillitis is a multifactorial disease associated with an aberrant tonsillar germinal center response to Group A Streptococcus.\n\nABSTRACTRecurrent Group A Streptococcus (GAS) tonsillitis (RT) is a common indication for pediatric tonsillectomy. Strep throat is highly prevalent among children; yet, it is unknown why some children develop RT. To gain insights into this classic childhood disease, we performed phenotypic, genotypic, and functional studies on pediatric GAS RT and non-RT tonsils. We observed significantly smaller germinal centers in GAS RT tonsils, and underrepresentation of GAS-specific germinal center follicular helper (GC Tfh) CD4+ T cells. RT children exhibited reduced antibody responses to GAS virulence factor SpeA. Risk and protective HLA Class II alleles for RT were identified. Finally, SpeA induced granzyme B+ GC Tfh cells in RT tonsils that had capacity to kill B cells. Together, these observations suggest that RT susceptibility can occur due to genetic differences that can result in aberrant GC Tfh cells and poor antibody responses to GAS SpeA.

immunology↗