Severe Acute Respiratory Syndrome-Associated Coronavirus Vaccines Formulated with Delta Inulin Adjuvants Provide Enhanced Protection while Ameliorating Lung Eosinophilic Immunopathology
Severe Acute Respiratory Syndrome-Associated Coronavirus Vaccines Formulated with Delta Inulin Adjuvants Provide Enhanced Protection while Ameliorating Lung Eosinophilic Immunopathology
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DOI：
10.1128/jvi.02980-14
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发表时间：
2015-03-01
影响因子：
5.4
通讯作者：
Petrovsky, Nikolai
中科院分区：
文献类型：
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作者：
Honda-Okubo, Yoshikazu;Barnard, Dale;Petrovsky, Nikolai
尽管非疫苗措施控制了严重急性呼吸综合征相关冠状病毒（SARS-CoV）的流行，但冠状病毒仍然是人类健康的主要威胁。因此，设计最佳的冠状病毒疫苗仍然是一个优先事项。这类疫苗带来了重大挑战：冠状病毒免疫力往往迅速减弱，需要保护的个体包括老年人，疫苗可能会加剧而不是预防冠状病毒肺部免疫病理学。为了解决这些问题，我们在小鼠模型中比较了一系列单独的重组刺突蛋白或灭活全病毒疫苗候选物，或者用明矾、CpG或Advax（一种新的基于δ菊粉的多糖佐剂）佐剂。虽然所有的疫苗保护免受致死性感染，佐剂的加入显着增加血清中和抗体滴度和降低肺病毒滴度在第3天攻毒后。尽管无佐剂或明矾配制的疫苗与攻击后第6天肺嗜酸性粒细胞免疫病理学显著增加相关，但在用δ菊粉佐剂配制的疫苗免疫的小鼠中未观察到这一点。含delta菊粉佐剂的疫苗对嗜酸性粒细胞免疫病理学的保护与增强的T细胞γ干扰素（IFN-γ）回忆应答相关性更好，而不是减少白细胞介素-4（IL-4）应答，这表明免疫病理学主要反映了疫苗诱导的Th 1应答不足。这项研究强调了基于诱导持久IFN-γ应答的能力选择佐剂对开发有效和安全的冠状病毒疫苗的至关重要性。重要的是，冠状病毒如SARS-CoV和中东呼吸综合征相关冠状病毒（MERS-CoV）导致高病死率，仍然是人类公共卫生的主要威胁，需要有效的疫苗。虽然已经鉴定了诱导保护性中和抗体的冠状病毒抗原，但冠状病毒疫苗存在一个独特的问题，即当被病毒感染时，免疫个体可发展成肺嗜酸性细胞病理学，该问题通过用明矾佐剂配制SARS-CoV疫苗而进一步加剧。这项研究表明，SARS-CoV刺突蛋白或灭活的全病毒疫苗与新的三角菊糖基多糖佐剂的配方增强了中和抗体滴度和对临床疾病的保护，但同时也防止了肺嗜酸性粒细胞免疫病理学的发展。它还表明，用δ菊粉佐剂实现的免疫是持久的，从而克服了冠状病毒免疫力迅速减弱的自然趋势。因此，delta菊粉佐剂可能提供开发更安全和更有效的冠状病毒疫苗的独特能力。
Although the severe acute respiratory syndrome-associated coronavirus (SARS-CoV) epidemic was controlled by nonvaccine measures, coronaviruses remain a major threat to human health. The design of optimal coronavirus vaccines therefore remains a priority. Such vaccines present major challenges: coronavirus immunity often wanes rapidly, individuals needing to be protected include the elderly, and vaccines may exacerbate rather than prevent coronavirus lung immunopathology. To address these issues, we compared in a murine model a range of recombinant spike protein or inactivated whole-virus vaccine candidates alone or adjuvanted with either alum, CpG, or Advax, a new delta inulin-based polysaccharide adjuvant. While all vaccines protected against lethal infection, addition of adjuvant significantly increased serum neutralizing-antibody titers and reduced lung virus titers on day 3 postchallenge. Whereas unadjuvanted or alum-formulated vaccines were associated with significantly increased lung eosinophilic immunopathology on day 6 postchallenge, this was not seen in mice immunized with vaccines formulated with delta inulin adjuvant. Protection against eosinophilic immunopathology by vaccines containing delta inulin adjuvants correlated better with enhanced T-cell gamma interferon (IFN-gamma) recall responses rather than reduced interleukin-4 (IL-4) responses, suggesting that immunopathology predominantly reflects an inadequate vaccine-induced Th1 response. This study highlights the critical importance for development of effective and safe coronavirus vaccines of selection of adjuvants based on the ability to induce durable IFN-gamma responses.IMPORTANCECoronaviruses such as SARS-CoV and Middle East respiratory syndrome-associated coronavirus (MERS-CoV) cause high case fatality rates and remain major human public health threats, creating a need for effective vaccines. While coronavirus antigens that induce protective neutralizing antibodies have been identified, coronavirus vaccines present a unique problem in that immunized individuals when infected by virus can develop lung eosinophilic pathology, a problem that is further exacerbated by the formulation of SARS-CoV vaccines with alum adjuvants. This study shows that formulation of SARS-CoV spike protein or inactivated whole-virus vaccines with novel delta inulin-based polysaccharide adjuvants enhances neutralizing-antibody titers and protection against clinical disease but at the same time also protects against development of lung eosinophilic immunopathology. It also shows that immunity achieved with delta inulin adjuvants is long-lived, thereby overcoming the natural tendency for rapidly waning coronavirus immunity. Thus, delta inulin adjuvants may offer a unique ability to develop safer and more effective coronavirus vaccines.