世界上第一種瘧疾疫苗的緩慢推出 – 愛滋防治宣導-財團法人台灣紅絲帶基金會

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世界上第一種瘧疾疫苗的緩慢推出

經過 30 年的發展，終於有了一種瘧疾疫苗。但可能需要數年時間才能將其送到需要它的孩子手中。

資料來源：展望/2022 年 12 月 19 日/自然/財團法人台灣紅絲帶基金會編譯

2019 年，加納、肯亞和馬拉威參加了 RTS,S 疫苗的試點研究。圖片來源：Amos Gumulira/AFP via Getty

John Bawa 在位於阿克拉的全球非營利組織 PATH 領導非洲疫苗實施工作，十多年來一直致力於研製第一種抗瘧疾疫苗。他已經習慣了聽到同樣的問題：「你的疫苗在哪裡」？因此，去年，當世界衛生組織 (WHO) 建議生活在受該病影響最嚴重的國家的兒童使用名為 RTS,S 並以 Mosquirix 銷售的疫苗時，「這對我們來說是一種極大的解脫」，他說。「現在我有了疫苗」。

世衛組織的建議是一個歷史性的里程碑。 RTS,S 研發歷時 30 年，不僅是第一個瘧疾疫苗，也是第一個針對任何寄生蟲病的疫苗。儘管注射的效果不大——第一年的效果約為 50%——但預計每年可挽救數萬人的生命。一項研究估計，如果疫苗在瘧疾負擔最重的國家推廣，每年可以預防 530 萬例病例和 24,000 例幼兒死亡。

《自然》期刊展望中的部分：兒童健康

但獲得這種好處需要時間。迄今為止，已有超過 100 萬兒童在加納、肯亞和馬拉威的試點研究中接種了一劑或多劑疫苗。這只是 30 多個國家需要它的 2,500 萬兒童的一小部分。其中許多國家可能需要數年時間才能接種第一劑疫苗。

專家估計，每年的需求量將達到 8,000 萬至 1 億劑。該疫苗的製造商葛蘭素史克 (GSK) 是一家總部位於英國布倫特福德的製藥公司，該公司已承諾在未來 3 年內交付 1,800 萬劑疫苗。對於眼睜睜看著這款疫苗在漫長研發過程中屢屢碰壁的人來說，供應問題讓人大失所望。

但是麻薩諸塞州波士頓的哈佛公共衛生學院的瘧疾研究員 Dyann Wirth正努力往好的方面看。有疫苗總比沒有好得多。 RTS,S 的批准「改變了關於疫苗對瘧疾是否可行的討論」，她說。這將為更好的疫苗鋪平道路。

漫長的延遲

近幾十年來，公共衛生工作者在對抗瘧疾方面取得了令人矚目的成就。 2000 年至 2019 年間，全球因瘧疾導致的死亡人數下降了約 40%。然而，這種疾病仍然是兒童死亡的首要原因之一。 2020 年，全球有 2.41 億例瘧疾病例和 62.7 萬例死亡。非洲約佔病例和死亡人數的 95%，其中 80% 是 5 歲以下兒童。

RTS,S 的作用是靶向瘧疾寄生蟲表面的一部分環子孢子蛋白。這個想法是，接種疫苗的人會產生抗體並在寄生蟲進入紅細胞之前將其殺死。但疫苗並不能提供完美的保護。在接種疫苗後的第一年，它對預防 5 至 17 個月大的兒童瘧疾臨床病例的有效性約為 50%。 4 年後，臨床發作的療效降至 36%，嚴重瘧疾的療效降至 32%。該疫苗還在 6 至 12 週齡的小嬰兒身上進行了測試，但功效較低，而且其益處被認為不足以證明其在該年齡組中的使用是合理的。

與保護性超過 90% 的麻疹或脊髓灰質炎疫苗相比，這些功效數字令人失望。但是，路易斯安那州新奧爾良杜蘭大學的流行病學家 Joshua Yukich 說：「當我們將其納入我們其他介入措施在預防嚴重瘧疾方面的有效性時，它並沒有看起來那麼糟糕」。「給一個人戴蚊帳並不能 100% 預防嚴重的瘧疾發作」。並且希望疫苗將被添加到已經到位的其他介入措施中。事實上，當研究人員將疫苗與藥物結合使用以在季節性傳播地區預防瘧疾時，這種結合提供了比單獨使用任何一種策略更高的疾病保護——大約 60%。

RTS,S 的 III 期試驗於 2014 年結束。對於大多數疫苗來說，這是批准和推出之前的最後一步。但疫苗需要通過世界衛生組織的資格預審計畫，該計畫證明用於低收入和中等收入國家的藥物和疫苗的安全性和有效性。當世衛組織免疫和瘧疾諮詢委員會開會討論疫苗時，一些成員表示擔憂。

該研究未能確定 RTS,S 對死亡率的影響。更重要的是，研究人員在接種疫苗的兒童中發現了腦膜炎病例，世衛組織委員會成員希望確定兩者之間沒有因果關係。他們還質疑在非洲推出四劑疫苗的可行性。劑量的時間與其他兒童疫苗的劑量並不完全一致，而且在他們出生後的第一年接種疫苗可能會很棘手。「人們非常懷疑非洲的醫療保健系統是否能夠以值得的方式提供這種疫苗」，Yukich 說。

因此，世界衛生組織沒有給 RTS,S 一個完整的建議，而是決定於 2019 年在加納、肯亞和馬拉威批准一項大規模試點研究。該研究直到 2023 年才正式結束，但到 2021 年 10 月，世衛組織及其顧問已有足夠的數據證明該疫苗是安全的、吸收良好且實施看起來可行（參見go.nature.com/3ilss7v）。

Wirth 說，在當時進行一項試點研究是有意義的——畢竟，這是人類使用過的第一種寄生蟲病疫苗。但她表示，質疑是否在安全性和緊迫性之間取得了適當的平衡是公平的。「II 期試驗的數據與試點研究的數據大致相同」，她說。 II 期結果發表於十多年前。在那段時期，「數十萬兒童患上了嚴重的瘧疾，其中許多人死亡」。

推出困境

WHO 的認可是讓 RTS,S 惠及需要它的兒童的重要一步，但這些兒童中的大多數不會很快受益。當世界衛生組織最初決定在 2015 年啟動試點研究時，葛蘭素史克關閉了他們在比利時瓦夫爾的 RTS,S 製造工廠。它直到 2019 年才重新開放，提高產量需要時間。

GSK承諾2023年交付400萬劑，2024年交付600萬劑，2025年交付800萬劑。到2026年，GSK的工廠年產量將達到1,500萬劑。 GSK 首席全球衛生官 Thomas Breuer 說：「這就是該設施所能生產的全部」。但這個數字只是預期需求的一小部分。

英國牛津大學詹納研究所所長 Adrian Hill 說：「僅在撒哈拉以南非洲地區就有 4,000 萬兒童出生在中度至高度傳播的瘧疾地區，而 RTS,S 需要四劑」。「那是每年 1.6 億劑」。世界衛生組織預測，需求量會更低——每年 1 億劑。但這兩項估計都代表了比葛蘭素史克計劃生產的疫苗多得多的數量。

GSK 宣布，到 2028 年，它將把製造 RTS,S 的技術轉讓給印度海得拉巴的生物技術公司 Bharat Biotech。這應該有助於增加供應，但有一個問題。 RTS,S 由兩部分組成：抗原 (RTS,S) 和稱為 AS01E 的佐劑，有助於增強免疫反應。 Bharat Biotech 將生產抗原，但 GSK 仍將提供佐劑。 AS01E 含有一種叫做皂苷的化學物質——具體來說，「一種特殊的皂苷，你只能從一種叫做 Quillaja saponaria 的樹中提取，這種樹主要生長在智利」，Hill 說。葛蘭素史克承諾每年供應多達 3,000 萬劑佐劑。「如果需要更多，我們會找到它」，布魯爾說。他指出，絕大多數這種皂苷都用於其他目的，例如化妝品，可能會被轉移。「佐劑不會成為瓶頸」，他說。

然而，在那之前，必須仔細分配現有的有限疫苗供應。這項任務落在了位於瑞士日內瓦的全球疫苗免疫聯盟 (Gavi) 的肩上，該聯盟幫助為世界上最貧窮國家的兒童接種疫苗。 2021 年 12 月，Gavi 董事會批准了 1.557 億美元用於從 2022 年到 2025 年推出 RTS,S。想要疫苗的國家可以向 Gavi 申請資金，這將考慮多種因素，包括每個國家的瘧疾負擔和部署疫苗的能力。通過 Gavi 接種疫苗的國家將根據其收入支付可變部分的費用。

只有試驗疫苗的三個國家有資格獲得第一輪資助。 Gavi 疫苗計畫負責人斯蒂芬·索斯勒 (Stephen Sosler) 表示：「我們希望確保能夠為他們提供足夠的供應，以便他們可以繼續他們的計畫而不會有任何停頓」。下一輪將於 2023 年 1 月結束。截至 11 月下旬，已有 21 個國家表示有興趣申請。全球疫苗免疫聯盟正在努力爭取在 2023 年底之前讓這些國家接種第一劑疫苗。由於供應非常有限，全球疫苗免疫聯盟將格外小心，以確保每一劑疫苗都能產生最大的影響，並且沒有任何浪費，索斯勒說。

試驗中的替代品

擁有多種疫苗將有助於緩解供應限制。 7 月，總部位於德國美因茨的生物技術公司 BioNTech 宣布，計畫在今年年底前啟動瘧疾 mRNA 疫苗的試驗。牛津大學正在開發的另一種瘧疾疫苗 R21 已經進入 III 期臨床試驗，如果證明安全有效，最快可在 2023 年投入使用。R21 使用與 RTS,S 相同的抗原，但 9 月 4 日發布的 R21 的 II 期試驗結果顯示它可能更有效。在布及納法索對大約 400 名兒童進行的一項試驗中，4 劑疫苗在 12 個月後提供了大約 75% 的預防瘧疾臨床病例的保護。

更多來自《 Nature 》期刊展望 (Outlooks)

這個數字聽起來令人印象深刻，但它是否能在 III 期試驗中站得住腳還不清楚。 II 期研究發生在西非，那裡的瘧疾傳播具有季節性。「9 月、10 月和 11 月是瘧疾的高峰期。我們在六月和七月接種疫苗」，希爾說，就在瘧疾季節來臨之前。但是「當你去一個一年中傳播超過 12 個月的地方時會發生什麼」？布及納法索納諾羅健康科學研究所 (IRSS) 區域主任 Halidou Tinto 說。

如果 R21 獲得批准，它可能會大大增加瘧疾疫苗的供應。世界上最大的疫苗製造商——位於浦那的印度生物製藥公司 Serum Institute——已經承諾每年生產超過 2 億劑疫苗，Tinto 稱這個數量「驚人」。當然，向低收入國家提供任何瘧疾疫苗都需要大量和持續的投資。 Bawa 說：「我們希望 COVID 所提供的那種支持，以及所有的資金和所有的興趣，都能得到支持」。但那還沒有發生。但他仍然希望它會。「對抗瘧疾是一場全球性的鬥爭」，他說。如果世界能夠消除瘧疾，「後人將永遠不會忘記我們」。

自然 612，S48-S49（2022 年）；doi: https://doi.org/10.1038/d41586-022-04343-7

本文是《自然展望：兒童健康》的一部分，關於這個內容這是一份在第三方資助下製作的獨立編輯增刊。。

參考文獻：

1.1. RTS,S Clinical Trials Partnership. Lancet 386, 31–45 (2015).

2.Hogan, A. B., Winskill, P. & Ghani, A. C. PLoS Med. 17, e1003377 (2020).

3.Chandramohan, D. et al. N. Engl. J. Med. 385, 1005–1017 (2021).

4.Datoo, M. S. et al. Lancet Infect. Dis. https://doi.org/10.1016/S1473-3099(22)00442-X (2022).

The slow roll-out of the world’s first malaria vaccine

After 30 years of development, there is finally a vaccine for malaria. But it might take years to get it to the children who need it.

OUTLOOK/19 December 2022/Nature

Ghana, Kenya and Malawi took part in a pilot study of the RTS,S vaccine in 2019.Credit: Amos Gumulira/AFP via Getty

John Bawa, who leads vaccine implementation in Africa at the global non-profit organization PATH in Accra, has been working for more than a decade on the first vaccine against malaria. And he has become used to hearing the same question: “Where is your vaccine?” So, last year, when the World Health Organization (WHO) recommended the use of the vaccine, known as RTS,S and marketed as Mosquirix, in children living in countries hardest hit by the disease, “it was a great relief for us”, he says. “Now I have my vaccine.”

The WHO’s recommendation was a historic milestone. RTS,S took 30 years to develop, and is not only the first malaria vaccine, but also the first vaccine for any parasitic disease. Although the efficacy of the shot is modest — about 50% in the first year1 — it is expected to save tens of thousands of lives each year. One study2 estimated that, if the vaccine were rolled out in countries with the highest burden of malaria, it could prevent 5.3 million cases and 24,000 deaths in young children each year.

Part of Nature Outlook: Children‘s health

But reaping that benefit will take time. So far, more than one million children have received one or more doses of the vaccine in a pilot study in Ghana, Kenya and Malawi. That’s just a fraction of the 25 million children in more than 30 countries who need it. It could be years before many of those countries get their first doses.

Specialists estimate that demand will be 80 million to 100 million doses per year. The vaccine’s manufacturer GlaxoSmithKline (GSK), a pharmaceutical company based in Brentford, UK, has promised to deliver 18 million doses over the next 3 years. For the people who have watched this vaccine hit roadblock after roadblock during its long period of development, the supply problems come as a disappointment.

But Dyann Wirth, a malaria researcher at the Harvard T.H. Chan School of Public Health in Boston, Massachusetts, is trying to look on the bright side. Having some vaccine is much better than having none. RTS,S approval “changed the conversation about whether vaccines were feasible for malaria”, she says. And that will pave the way for better vaccines.

The long delay

Public-health workers have made impressive gains against malaria in recent decades. Between 2000 and 2019, global deaths attributable to malaria fell by around 40%. Yet the disease remains one of the top causes of death among children. In 2020, the world saw 241 million cases of malaria and 627,000 deaths. Africa accounted for around 95% of the cases and deaths, and 80% of those deaths were children under 5.

RTS,S works by targeting a portion of the circumsporozoite protein on the surface of the malaria parasite. The idea is that a vaccinated individual will generate antibodies and kill off the parasite before it can enter red blood cells. But the vaccine does not grant perfect protection. In the first year after vaccination, it is about 50% effective in preventing clinical cases of malaria in children aged 5 to 17 months. After 4 years, efficacy drops to 36% for clinical episodes and 32% for severe malaria. The vaccine has also been tested in younger infants aged between 6 and 12 weeks, but efficacy was lower and the benefits were not deemed significant enough to justify its use in this age group.

Those efficacy numbers are disappointing when compared with vaccines for measles or polio, which are more than 90% protective. But “when we put that in the spectrum of how effective our other interventions are at preventing severe malaria, it’s not as bad as it seems”, says Joshua Yukich, an epidemiologist at Tulane University in New Orleans, Louisiana. “It’s not like giving a person a bed net prevents 100% of severe malaria episodes.” And the hope is that the vaccine will be added to other interventions that are already in place. In fact, when researchers combined the vaccine with medications to prevent malaria in areas with seasonal transmission, the combination offered much higher protection against the disease than either strategy alone3 — around 60%.

The phase III trial for RTS,S wrapped up in 2014. For most vaccines, this is the final step before approval and roll-out. But the vaccine needed to pass the WHO’s prequalification programme, which certifies the safety and efficacy of medicines and vaccines destined for low- and middle-income countries. When the WHO’s advisory committee on immunization and malaria met to discuss the vaccine, some members had concerns.

The study had not been able to determine the impact of RTS,S on mortality. What’s more, researchers had picked up cases of meningitis in children who had received the vaccine, and the WHO committee members wanted to be sure there wasn’t a causal link. They also questioned the feasibility of rolling out a four-dose vaccine in Africa. The timing of the doses doesn’t entirely line up with those for other childhood vaccines, and reaching children after their first year of life can be tricky. “People were very sceptical that an African health-care system was going to be able to deliver that vaccine in a way that was worth it,” Yukich says.

So rather than giving RTS,S a full recommendation, the WHO decided to green-light a large-scale pilot study in 2019 in Ghana, Kenya and Malawi. That study doesn’t officially wrap up until 2023, but by October 2021 the WHO and its advisers had enough data to see that the vaccine was safe, uptake was good and implementation looked feasible (see go.nature.com/3ilss7v).

Running a pilot study made sense at the time, Wirth says — this was the first vaccine for parasitic disease ever used in people, after all. But she says it’s fair to question whether the right balance was struck between safety and urgency. “Data from the phase II trials is more or less the same as the data from the pilot studies,” she says. The phase II results were published more than a decade ago. During that period “hundreds of thousands of children suffered serious malaria, and many of them died”.

Roll-out woes

The WHO’s endorsement is an important step in getting RTS,S to the children who need it, but most of those children won’t benefit any time soon. When the WHO initially decided to launch the pilot study in 2015, GSK closed their RTS,S manufacturing plant in Wavre, Belgium. It didn’t reopen until 2019, and ramping up production will take time.

GSK has promised to deliver 4 million doses in 2023, 6 million in 2024 and 8 million in 2025. By 2026, GSK’s plant will produce 15 million doses a year. “That is all the facility can produce,” says Thomas Breuer, chief global health officer at GSK. But that number is a fraction of the expected demand.

“There are 40 million kids born in sub-Saharan Africa alone in malarious areas of moderate to high transmission,” says Adrian Hill, director of the Jenner Institute at the University of Oxford, UK, and RTS,S requires four doses. “That’s 160 million doses a year.” The WHO predicts that demand will be lower — in the realm of 100 million doses per year. But both estimates represent much more vaccine than GSK plans to produce.

GSK has announced that, by 2028, it will transfer the technology to manufacture RTS,S to Bharat Biotech, a biotechnology company in Hyderabad, India. This should help to bolster supplies, but there’s a catch. RTS,S is composed of two parts: the antigen (RTS,S) and an adjuvant called AS01E, which helps to boost the immune response. Bharat Biotech will manufacture the antigen, but GSK will still supply the adjuvant. AS01E contains a type of chemical called a saponin — specifically, “a particular saponin you can only extract from a tree called Quillaja saponaria, which grows primarily in Chile”, Hill says. GSK has promised to supply up to 30 million doses of adjuvant per year. “If more is needed, we will find it,” Breuer says. He points out that the vast majority of this saponin is used for other purposes, such as in cosmetics, and could be diverted. “The adjuvant will not be the bottleneck,” he says.

Until then, however, the limited supplies of vaccine that do exist will have to be carefully distributed. That task falls to Gavi, the Vaccine Alliance, in Geneva, Switzerland, which helps to vaccinate children in the world’s poorest countries. In December 2021, Gavi’s board approved US$155.7 million for the roll-out of RTS,S from 2022 to 2025. Countries that want the vaccine can apply for funding from Gavi, which will consider a variety of factors, including each nation’s malaria burden and capacity to deploy the vaccine. Countries that receive vaccines through Gavi will pay a variable portion of the cost, depending on their income.

Only the three countries that piloted the vaccine were eligible for the first round of funding. “We want to make sure that we can get sufficient supplies to them so that they can continue their programmes without having any pause,” says Stephen Sosler, head of vaccine programmes at Gavi. The next round will close in January 2023. As of late November, 21 countries had expressed interest in applying. Gavi is working hard to try to get those countries their first doses by the end of 2023. Because supplies are so limited, Gavi will take extra care to make sure that each dose has the maximum impact and that there isn’t any waste, Sosler says.

Alternatives on trial

Having multiple vaccines would help to ease supply constraints. In July, the biotechnology company BioNTech, based in Mainz, Germany, announced plans to launch trials of an mRNA vaccine for malaria by the end of this year. Another malaria vaccine, being developed at the University of Oxford, called R21, is already in phase III clinical trials and, if proven to be safe and effective, it could be deployed as soon as 2023. R21 uses the same antigen as RTS,S, but the results of R21’s phase II trials, released in September4, suggest that it might be more effective. In a trial of about 400 children in Burkina Faso, 4 doses provided around 75% protection against clinical cases of malaria after 12 months.