Boosted Influenza-Specific T Cell Responses after H5N1 Pandemic Live Attenuated Influenza Virus Vaccination

Abstract

BackgroundIn a phase I clinical trial, a H5N1 pandemic live attenuated influenza virus (pLAIV) VN2004 vaccine bearing avian influenza H5N1 hemagglutinin (HA) and NA genes on the A/Ann Arbor cold-adapted vaccine backbone displayed very restricted replication. We evaluated T cell responses to H5N1 pLAIV vaccination and assessed pre-existing T cell responses to determine whether they were associated with restricted replication of the H5N1 pLAIV.MethodELISPOT assays were performed using pools of overlapping peptides spanning the entire H5N1 proteome and the HA proteins of relevant seasonal H1N1 and H3N2 viruses. We tested stored peripheral blood mononuclear cells (PBMCs) from 21 study subjects who received two doses of the H5N1 pLAIV. The PBMCs were collected 1 day before and 7 days after the first and second pLAIV vaccine doses, respectively.ResultT cell responses to conserved internal proteins M and NP were significantly boosted by vaccination (p = 0.036). In addition, H5N1 pLAIV appeared to preferentially stimulate and boost pre-existing seasonal influenza virus HA-specific T cell responses that showed low cross-reactivity with the H5 HA. We confirmed this observation by T cell cloning and identified a novel HA-specific epitope. However, we did not find any evidence that pre-existing T cells prevented pLAIV replication and take.ConclusionWe found that cross-reactive T cell responses could be boosted by pLAIV regardless of the induction of antibody. The impact of the “original antigenic sin” phenomenon in a subset of volunteers, with preferential expansion of seasonal influenza-specific but not H5N1-specific T cell responses merits further investigation.

Broad and strong memory CD4+and CD8+T cells induced by SARS-CoV-2 in UK convalescent COVID-19 patients

“…IFN-γ ELISpot assays were performed using either freshly isolated or cryopreserved PBMCs as described previously. No significant difference was observed between responses generated by fresh or cryopreserved PBMCs as described previously 17,18 .…”

Immunogenicity and protective efficacy of prime-boost immunization in mice vaccinated with live and inactivated influenza A (H5N1) vaccines

“…В отношении CD8 + IFNγ + клеток, максимально выраженный эффект со ста тистически достоверным приростом CD8 + на 7 день после повторной иммунизации в нашем эксперименте наблюдался только у схемы ЖГВ/ИГВ. Возможно, такой эффект связан с различной скоростью клеточного иммунного ответа при введении разных антигенов [15,22] и может быть подробнее изучен в отдельном кинетическом эксперименте. Данные, полученные в клинических испытаниях на волонтерах, свидетельствуют о способности как ЖГВ А (H5N2) [18], так и ИГВ А (H5N1) [14] формировать дологоживущие клетки иммунологической памяти, но их фенотипы и антигенная специфичность, судя по имеющимся данным, различаются, что также требует отдельного подробного исследования.…”

Live Attenuated Cold-Adapted Influenza Vaccines

“…This was surprising for two reasons: first, because pLAIVs had replicated well and were immunogenic in mice and ferrets, and, second, because the healthy adults who received the pLAIV had no prior exposure to avian influenza viruses. Several potential explanations were investigated including the sialic acid receptor preference of the pLAIVs and inhibition of vaccine virus replication by anti-NA antibodies induced against human NAs cross-reacting with avian NAs or by cross-reactive T-cell responses (Peng et al 2015), but none provided a satisfactory explanation for the restricted replication and immunogenicity in humans.…”