Improved Immune Responses in Young and Aged Mice with Adjuvanted Vaccines against H1N1 Influenza Infection

Abstract

Elderly people are at high risk for influenza-related morbidity and mortality due to progressive immunosenescence. While toll-like receptor (TLR) agonist containing adjuvants, and other adjuvants, have been shown to enhance influenza vaccine-induced protective responses, the mechanisms underlying how these adjuvanted vaccines could benefit the elderly remain elusive. Here, we show that a split H1N1 influenza vaccine (sH1N1) combined with a TLR4 agonist, glucopyranosyl lipid adjuvant formulated in a stable oil-in-water emulsion (GLA-SE), boosts IgG2c:IgG1 ratios, enhances hemagglutination inhibition (HAI) titers, and increases protection in aged mice. We find that all adjuvanted sH1N1 vaccines tested were able to protect both young and aged mice from lethal A/H1N1/California/4/2009 virus challenge after two immunizations compared to vaccine alone. We show that GLA-SE combined with sH1N1, however, also provides enhanced protection from morbidity in aged mice given one immunization (based on change in weight percentage). While the GLA-SE-adjuvanted sH1N1 vaccine promotes the generation of cytokine-producing T helper 1 cells, germinal center B cells, and long-lived bone marrow plasma cells in young mice, these responses were muted in aged mice. Differential in vitro responses, dependent on age, were also observed from mouse-derived bone marrow-derived dendritic cells and lung homogenates following stimulation with adjuvants, including GLA-SE. Besides enhanced HAI titers, additional protective factors elicited with sH1N1 + GLA-SE in young mice were observed, including (a) rapid reduction of viral titers in the lung, (b) prevention of excessive lung inflammation, and (c) homeostatic maintenance of alveolar macrophages (AMs) following H1N1 infection. Collectively, our results provide insight into mechanisms of adjuvant-mediated immune protection in the young and elderly.

Combination of STING Pathway Agonist With Saponin Is an Effective Adjuvant in Immunosenescent Mice

“…The levels of the vaccine-specific immunoglobulins were also determined to estimate the differences in the magnitude of antibody response. The HAI titers, which are typically used as a correlate of protection (47), were almost undetectable in any of the aged animals, consistent with previously reported observations (17,48), and thus not very useful.…”

“…The low protective efficacy of influenza vaccines in the aged population (40)(41)(42)(43) is driving an intensive search for adjuvants that will elicit a more effective immune response (17,(44)(45)(46). Purified subunit vaccines such as used in this study are known for their good safety profile and low reactogenicity but also for relatively lower immunogenicity, especially in the aged, compared with whole inactivated virus.…”

“…We employed an aged mouse model that has been shown to recapitulate age-related changes in humans (12,13) including responses to influenza infection and vaccination (14,15). Several adjuvant formulations have been previously shown to increase protective efficacy of hemagglutinin (HA)based influenza vaccines in aged mice, but these formulations required use of complex preparation procedures and some included more than one dose of vaccine (16)(17)(18)(19). However, influenza vaccine is administered only once during the annual vaccination campaigns.…”

Memory CD4+ T cells enhance B‐cell responses to drifting influenza immunization

“…This absence of robust HA‐specific CD4 + T‐cell reactivity to A/CA HA in C57BL/6 mice was further confirmed by IFN‐γ ELISPOT and HA reactivity to A/CA rHA (recombinant HA) in CB6F1 mice has been previously established (Supporting Information Fig. B) . Conversely, CB6F1 mice infected with either A/CA or A/PR8 demonstrated CD4 + T‐cell reactivity with A/CA peptides (Fig.…”

Efeito da exposição à hidroquinona na resposta imune adaptativa induzida pela vacina contra a influenza

“…Trabalhos relacionam a importância desta subclasse de IgG na proteção contra o Influenza A, onde vacinas que a induzem tem maior eficiência em proteger camundongos contra a infecção e, ainda, animais que possuem menores títulos de IgG2c tem maior perda de peso e mortalidade frente ao desafio imunológico (BALDWIN et al, 2018;JIAN et al, 2013;JIANG et al, 2016;KANG et al, 2004;KOPECKY-BROMBERG et al, 2009;WELDON et al, 2012 O mecanismo de toxicidade da HQ está relacionado, pelo menos em parte, pela sua capacidade de gerar estresse oxidativo (IARC, 1987;JURICA et al, 2017;MCGREGOR, 2008;SYDER, 2007;SUBRAHMANYAM et al, 1991 FUENTE, 2016;DE LA FUENTE et al, 2011). O peróxido de hidrogênio é fator importante para a ativação e diferenciação das células B, onde células na ausência deste composto apresentam prejuízo nestes processos celulares (BERTOLOTTI et al, 2016;POLIKOWSKY et al, 2015); As células T, assim como as B, necessitam das ERO para serem ativadas, expandidas e exercerem sua função (CEMERSKI et al, 2002;DEVADAS et al, 2002;GELDERMAN et al, 2006;JACKSON et al, 2004).…”