呼吸道融合病毒 (RSV) 浪潮重創醫院——但疫苗和治療即將問世

由於呼吸系統疾病助長了「三重病」，輝瑞和葛蘭素史克競相獲得批准。

資料來源：雷切爾·費爾班克 / 2022 年 12 月 15 日 / 自然 / 財團法人台灣紅絲帶基金會編譯

一名護士在德國斯圖加特奧爾加醫院的重症監護室照顧一名感染 RSV 的兒童。

圖片來源：Marijan Murat/dpa/Alamy

 

在過去的幾個月裡，呼吸道融合病毒 (RSV) 在美國和歐洲以驚人的速度將 5 歲以下兒童送往醫院。 隨著兒科病房的人滿為患，醫生們正在應對 RSV、流感和 COVID-19 的「三重病」，一些人一直在呼籲宣布進入緊急狀態。

RSV 會使肺部最小的氣道發炎，是三種呼吸道疾病中唯一一種尚未獲得批准疫苗的疾病——但這種情況可能很快就會改變。 上週，輝瑞製藥公司宣布，美國食品和藥物管理局 (FDA) 已同意優先審查其 RSV 疫苗，該疫苗將接種給 60 歲以上的成年人。 如果獲得批准——最快可能在 5 月發生——它可能成為第一個獲得批准的 RSV 疫苗。 同樣的疫苗在針對孕婦的臨床試驗中也顯示出針對 RSV 的積極結果，輝瑞公司表示將在今年年底前尋求對這一群體的批准。

《自然》回顧了 RSV 疫苗是如何出現的，並展望了它們將如何改變公共衛生格局。

幾十年來，RSV 一直是一個問題。 為什麼現在才出現疫苗？

在 1960 年代一次特別明顯的失敗之後，開發 RSV 疫苗的努力大幅受挫。 研究人員開發了一種含有 RSV 顆粒的疫苗，這些顆粒經過化學滅活，因此病毒無法複製。 但當他們在臨床試驗中對嬰兒進行注射測試時，卻以悲劇告終：兩名嬰兒死亡。 德克薩斯大學奧斯汀分校的結構生物學家 Jason McLellan 說，起初，嬰兒對疫苗的耐受性很好。 但在下一個感冒和流感季節，80% 的兒童在接種疫苗後又感染了 RSV，病情嚴重到需要住院治療。 相比之下，只有 5% 的接受安慰劑並隨後感染 RSV 的兒童最終住院。

這一失敗停止了開發 RSV 疫苗的努力，因為科學家們正在努力了解發生了什麼。

研究人員是如何克服這一失敗的？

研究人員沒有繼續嘗試用滅活病毒製造疫苗，而是嘗試製造一種基於蛋白質的疫苗，其中使用病毒的分離成分（例如表面蛋白）來觸發保護性免疫反應。 當包括 McLellan 在內的科學家對 RSV 表面發現的一種分子 F 蛋白的不同構象進行表徵時，一項重大突破就出現了。 蛋白F有助於將病毒和宿主細胞的細胞膜結合在一起，使病毒可以感染細胞。

蛋白 F 以兩種形式存在：高度穩定的融合後形式和不穩定的融合前形式。 在感染期間，當病毒和宿主細胞聚集在一起時，蛋白質呈現融合前形式，一旦感染發生，就會轉變為第二種形式。

Prefusion F 是「一種非常不穩定的蛋白質」，但「它是完全活躍的，並誘導最強烈的免疫反應」，因此它是製造有效疫苗所需要的，貝勒學院的病毒學家 Pedro Piedra 說 德克薩斯州休斯頓的醫學博士，其研究重點是減輕嬰兒呼吸道病毒引起的疾病負擔。

McLellan 和許多合作者最終對預融合形式的結構進行了表徵，然後研究出如何穩定它 。 這促進了疫苗的開發，並為潛在的基於抗體的療法打開了大門。 許多公司現在都在研發 RSV 疫苗，輝瑞和葛蘭素史克的版本最接近政府監管機構的批准。

這些疫苗會成功嗎？

總部位於紐約市的輝瑞公司在今年早些時候宣布了其候選疫苗的兩項試驗取得成功的 III 期結果。 在一項試驗中，該公司將疫苗接種給孕婦以提高她們的總抗體數量，其想法是這些抗體隨後會轉移到她們的嬰兒身上。

輝瑞公司在一份新聞稿中報告說，該策略在嬰兒出生後 90 天內對重症 RSV 病例的療效為81.8%。

 

由於「三重病」的疾病循環，伍斯特麻州大學紀念醫療中心等醫療設施的運行超出正常水平。

圖片來源：Suzanne Kreiter/Boston Globe via Getty

根據美國疾病控制和預防中心 (CDC) 的數據，在美國，RSV 通常每年平均將 58,000 至 80,000 名 5 歲以下兒童送往醫院。 McLellan 說，嬰兒最有可能在兩個半月大左右因 RSV 住院，此時他們的肺部仍在發育。 西雅圖華盛頓大學傳染病專家 Helen Chu 說，嬰幼兒感染 RSV 的主要風險「與氣道較小有很大關係」。

CDC 表示，RSV 對 65 歲以上的成年人也很危險，導致美國每年平均有 60,000-120,000 人住院。 在輝瑞公司的另一項 III 期試驗中，據報導該疫苗在 60 歲以上的成年人中預防嚴重疾病的有效性為 85.7%。全球總部位於倫敦的 GSK 也報告了 RSV 疫苗的成功 III 期結果 在 60 歲以上的成年人中進行了測試，預防嚴重疾病的有效性為 94.1%。

輝瑞和葛蘭素史克現在將競相獲得批准； 葛蘭素史克上個月宣布，FDA 將對其疫苗給予優先審查。 與輝瑞一樣，最早可能在 5 月獲得批准。

但喬治亞州亞特蘭大莫爾豪斯醫學院的病毒學家和免疫學家 Barney Graham 警告說，疫苗「不會讓 RSV 消失」，他與 McLellan 就預融合 F 進行了合作。他補充說，疫苗的作用是保護一些最脆弱的群體，包括非常年輕和非常年老的人。

於此同時，還有其他治療方法可以抑制 RSV 嗎？

在這個月之前，只有一種藥物可以對付 RSV。 最初由位於馬里蘭州蓋瑟斯堡的 MedImmune 製藥公司開發的單克隆抗體 palivizumab 可以作為預防藥物每月給藥一次，以減輕嬰幼兒疾病的嚴重程度。 考慮到成本、必要的給藥頻率以及必須注射的事實，醫生僅將帕利珠單抗用於高危嬰兒和兒童。 另一種名為 nirsevimab 的單克隆抗體由英國劍橋的阿斯利康公司和巴黎的賽諾菲公司開發，今年早些時候成功完成了 III 期試驗。 它的優點是一劑疫苗可為嬰兒提供五個月的預防嚴重疾病的保護。 歐盟委員會上個月批准了它，FDA 正在審查它。

格雷厄姆說，很快就會有許多工具可以幫助對抗困擾父母數十年的疾病。「這是一個重大突破」。

doi: https://doi.org/10.1038/d41586-022-04434-5

 

參考文獻：

1.Kim, H. Y. et al. Am. J. Epidemiol. 89, 422–434 (1969).

2.McLellan, J. S. et al. Science 340, 1113–1117 (2013).

3.Hammitt, L. L. et al. N. Engl. J. Med. 386, 837–846 (2022).

 

 

 

 

 

 

 

 

 

 

 

 

 

RSV wave hammers hospitals — but vaccines and treatments are coming

As the respiratory illness helps to fuel a ‘tripledemic’, Pfizer and GSK race to get jabs approved.

Rachel Fairbank / 15 December 2022 / Nature 

 

 

A nurse cares for a child infected with RSV in the intensive care unit at Olga Hospital in Stuttgart, Germany.Credit: Marijan Murat/dpa/Alamy

In the past few months, the respiratory syncytial virus (RSV) has been sending children under the age of 5 to hospital at alarming rates in the United States and Europe. As paediatric units fill beyond capacity, and physicians contend with a ‘tripledemic’ of RSV, influenza and COVID-19, some have been calling for a state of emergency to be declared.

 

Why is strep A surging — and how worried are scientists?

 

RSV, which inflames the smallest airways of the lungs, is the only one of the three respiratory illnesses for which there are not yet any approved vaccines — but that could soon change. Last week, the pharmaceutical company Pfizer announced that the US Food and Drug Administration (FDA) had agreed to review its RSV vaccine, to be administered to adults over the age of 60, as a priority. If approved — which might happen as soon as May — it could be the first sanctioned jab for RSV. The same vaccine has also shown positive results against RSV in a clinical trial in pregnant people, and Pfizer has said it will seek approval for this group by the end of the year.

Nature looks back at how vaccines for RSV emerged, and ahead to how they are about to change the public-health landscape.

RSV has been a problem for decades. Why are vaccines only emerging now?

Efforts to develop an RSV vaccine were set back substantially after a particularly notable failure in the 1960s. Researchers had developed a vaccine containing RSV particles that were chemically inactivated so that the virus couldn’t replicate. But when they tested the shot in infants in a clinical trial, it ended in tragedy: two babies died. At first, the infants tolerated the vaccine well, says Jason McLellan, a structural biologist at the University of Texas at Austin. But during the next cold and flu season, 80% of the children who had received a shot and then subsequently caught RSV became so ill they were hospitalized1. By comparison, only 5% of children who received the placebo and then caught RSV ended up in hospital.

The failure halted efforts to develop an RSV vaccine, as scientists worked to understand what had happened.

How did researchers overcome this failure?

Rather than continue trying to make a vaccine from inactivated virus, researchers attempted to make a protein-based vaccine, in which an isolated component of the virus, such as a surface protein, is used to trigger a protective immune response. A major breakthrough came when scientists, including McLellan, characterized the different conformations of protein F, a molecule found on the surface of RSV. Protein F helps to bring together the membranes of the virus and the host cell, so that the virus can infect the cell.

Protein F exists in two forms: a postfusion form, which is highly stable, and a prefusion form, which is not. The protein takes on the prefusion form during infection, when the virus and host cell are coming together, and transitions to the second form once infection has taken hold.

Prefusion F is “a very unstable protein”, but “that is what is fully active, and induces the most robust immune response”, so it was what was needed to make an effective vaccine, says Pedro Piedra, a virologist at Baylor College of Medicine in Houston, Texas, whose research focuses on reducing the burden of illness caused by respiratory viruses in infants.

McLellan and a number of collaborators eventually characterized the structure of the prefusion form and then worked out how to stabilize it. This enabled vaccine development, as well as opening the door to potential antibody-based therapies. A number of companies now have RSV vaccines in the pipeline, with versions from Pfizer and GSK being the closest to approval by government regulators.

Will those vaccines succeed?

Pfizer, which has headquarters in New York City, announced successful phase III results from two trials of its vaccine candidate earlier this year. In one trial, the firm gave the vaccine to pregnant people to boost their total antibody numbers, the idea being that those antibodies would then get transferred to their infants.

Pfizer reported in a press release that this strategy had an efficacy of 81.8% against severe cases of RSV in the infants for the 90 days after birth.

 

Medical treatment facilities such as the UMass Memorial Medical Center in Worcester are operating above normal capacity because of a ‘tripledemic’ of illnesses circulating.Credit: Suzanne Kreiter/Boston Globe via Getty

In the United States, RSV usually sends an average of 58,000–80,000 kids under the age of 5 to hospital each year, according to the US Centers for Disease Control and Prevention (CDC). Infants are most likely to be hospitalized with RSV around two and a half months of age, when their lungs are still developing, McLellan says. The major risk for infants and young children catching RSV “has a lot to do with having smaller airways”, says Helen Chu, an infectious-disease specialist at the University of Washington in Seattle.

RSV can also be dangerous for adults over the age of 65, resulting in an average of 60,000–120,000 hospitalizations per year in the United States, says the CDC. In Pfizer’s other phase III trial, the vaccine was reported to have an efficacy of 85.7% at preventing severe disease in adults over the age of 60. GSK, which has global headquarters in London, has also reported successful phase III results for an RSV vaccine tested in adults over the age of 60, which had an efficacy of 94.1% at preventing severe disease.

Pfizer and GSK will now race for approval; GSK announced last month that the FDA will give its vaccine priority review. As with Pfizer, approval could come as early as May.

But the vaccines are “not going to make RSV go away”, warns Barney Graham, a virologist and immunologist at Morehouse School of Medicine in Atlanta, Georgia, who collaborated with McLellan on prefusion F. What the vaccines will do, he adds, is protect some of the most vulnerable groups, including the very young and very old.

In the meantime, can any other treatments curb RSV?

Before this month, there was only one drug to tackle RSV. The monoclonal antibody palivizumab, originally developed by the pharmaceutical firm MedImmune, in Gaithersburg, Maryland, can be administered monthly as a prophylactic to reduce the severity of illness in infants and young children. Given the cost, necessary frequency of doses and the fact that it must be injected, physicians give palivizumab only to high-risk infants and children. Another monoclonal antibody, called nirsevimab and developed by companies AstraZeneca in Cambridge, UK, and Sanofi in Paris, finished phase III trials successfully earlier this year3. Its advantage is that one dose offers five months of protection against severe disease in infants. The European Commission approved it last month, and the FDA is reviewing it.

A number of tools could soon be available to help combat a disease that has haunted parents for decades, Graham says. “This is a major breakthrough.”

doi: https://doi.org/10.1038/d41586-022-04434-5

References

4.Kim, H. Y. et al. Am. J. Epidemiol. 89, 422–434 (1969).

5.McLellan, J. S. et al. Science 340, 1113–1117 (2013).

6.Hammitt, L. L. et al. N. Engl. J. Med. 386, 837–846 (2022).