猴痘疫苗似乎有效，但研究結果憂喜參半
資料來源：Liz Highleyman / 2022 年 10 月 13 日 /aidsmap / 財團法人台灣紅絲帶基金會編譯
圖片來源：新非洲/Shutterstock.com
MVA-BN 天花和猴痘疫苗在歐洲以 Imvanex 和在美國以 Jynneos 的形式出售，現已在多個國家廣泛推廣，但其在實際使用中的有效性仍存在疑問。
美國最近的一項分析顯示，接種疫苗的男性患猴痘的可能性降低了約 14 倍，但專家表示，在僅依靠疫苗接種來遏制猴痘爆發之前，還需要進行更多的研究。
歐洲和美國在非流行國家持續爆發的猴痘疫情在夏末達到頂峰後已顯著放緩。截至 10 月 10 日，英國衛生安全局 (UKHSA) 已確定 3,673 例確診或可能病例，其中包括上個月報告的 121 例。截至 10 月 12 日，美國疾病控制與預防中心 (CDC) 已在美國記錄了 27,022 例病例，在全球記錄了 72,400 多例病例。疫情爆發五個月後，猴痘仍以壓倒性優勢影響男男性行為者。
英國在 5 月份出現了首例疫情，是最先報告疫情機轉的國家之一。 8 月下旬，世界衛生組織報告說，全球新病例下降了 21%。但包括拉丁美洲在內的一些地區繼續出現大量新病例。
衛生官員和倡導者將這種下降歸因於多種因素，包括感染後的自然免疫力、疫苗接種和行為改變。 CDC最近的一項調查發現，大約一半的男同性戀、雙性戀和其他男男性行為者表示他們已經做出改變，例如減少性伴侶。最新的 UKHSA 技術報告指出，兩種性傳播感染，志賀氏菌和性病性淋巴肉芽腫也有所下降，證實了行為改變。
但猴痘疫苗在現實世界中的有效性尚未確定。
Bavarian Nordic 的 MVA-BN 疫苗使用弱化的牛痘病毒株，被開發為活病毒 ACAM2000 天花疫苗的更安全替代品。猴痘與天花有關，兩者都可以使用相同的疫苗。 1980年天花被根除後，常規天花疫苗接種停止，這促進了猴痘的傳播。由於猴痘病毒的潛伏期很長，疫苗既可用作暴露後長達兩週的暴露後預防，也可用作高危人群的暴露前預防。
MVA-BN 被批准為間隔一個月透過皮下注射系列給藥兩劑。為了擴大有限的疫苗供應，一些國家轉而在皮膚上層下進行皮內注射，這樣一瓶疫苗可以分成五劑。 2015 年的一項研究顯示，皮下或皮內注射的抗體反應相似，美國國立衛生研究院贊助的一項新臨床試驗將觀察小瓶是否可以進一步分成十劑。無論採用何種給藥方法，參與者都將在第一次給藥後一個月接受第二次給藥。
MVA-BN 在非人類靈長類動物中針對猴痘進行了測試。雖然它降低了出現症狀性疾病和死亡的可能性，但它並不能可靠地預防感染。然而，在這次疫情爆發之前，對人類的研究僅限於免疫原性研究，即觀察疫苗接種後的抗體水平。
例如，在 2019 年發表的一項 III 期試驗中，隨機分配接受 MVA-BN 或 ACAM2000 的人具有相當的抗體反應。 1980 年代在剛果民主共和國的研究發現，在停止接種天花疫苗之前接種過天花疫苗的人感染猴痘的可能性降低了 85%。因為 MVA-BN 產生類似的免疫反應，所以假設它會提供類似的保護。但當前爆發的一些病例發生在以前接種過天花疫苗的人群中。儘管自 2017 年以來一直在奈及利亞爆發猴痘，但 MVA-BN 尚未在奈及利亞進行過測試。剛果民主共和國正在進行針對高危醫護人員的疫苗試驗，但尚未報告結果。
MVA-BN 比舊的複制病毒天花疫苗更安全且耐受性更好，後者會導致嚴重的副作用並產生脫落活病毒的病變。對於免疫功能低下的人、孕婦、皮膚病患者或愛滋病毒感染者，較舊的疫苗被認為是不安全的。相比之下，MVA-BN 最常見的副作用是輕微的注射部位反應。皮內給藥會引起更多的瘙癢和發紅。
關於 MVA-BN 的幾個問題仍有待回答。不知道保護能持續多長時間，儘管疫苗接種或之前的猴痘感染被認為可以提供長期免疫。從歷史上看，猴痘通常在同一家庭成員之間或透過與動物接觸傳播。目前尚不清楚該疫苗對性傳播的保護效果如何。 2015 年的一項研究發現，具有足夠 CD4 計數的 HIV 陽性者對 MVA-BN 反應良好，但對 CD4 計數低的人的反應知之甚少。
當前爆發疫情的研究
為了更多地了解現實世界的有效性，CDC 研究人員分析了符合接種猴痘疫苗條件的男性的結果。該研究發表在 CDC 的發病率和死亡率週報上，基於 7 月 31 日至 9 月 3 日期間發生的 5,402 例猴痘病例，這段時間疫苗在美國廣泛使用，但大多數人只接種了第一劑。
CDC 主任 Rochelle Walensky 博士在最近的一次媒體簡報中說明報告，初步結果顯示，至少兩週前接種單劑疫苗的男性減少感染猴痘的可能性是未接種疫苗的合格男性的 14 倍。但該分析無法控制干擾因素。例如，早期接種疫苗的男性可能也改變了他們的性行為。
研究作者寫道：「這一早期發現顯示，單劑 Jynneos 疫苗可以對猴痘感染提供一定的保護」。「這種保護的程度和持久性尚不清楚，建議有資格接種猴痘疫苗的人接受完整的兩劑系列」。
「雖然疫苗確實提供了一些免疫力，但它並不能完全預防感染，尤其是在只注射一劑之後」。
以預印本形式發表的一項規模較小的以色列研究調查了 1,970 名符合接種疫苗條件的男性的結果，這些男性要麼正在接受 HIV PrEP，要麼是 HIV 陽性並且最近患有 STI。其中，873 人在 7 月 31 日至 8 月 18 日期間接種了一劑 MVA-BN 疫苗，並進行了至少 25 天的追蹤。 3 名接種疫苗和 15 名未接種疫苗的男性感染了猴痘。儘管病例數很少且信賴區間很寬（從 24% 到 94%），但疫苗有效性估計為 79%。「我們的研究結果顯示，單劑量的 MVA 與高危人群感染猴痘病毒的風險顯著降低有關」，研究人員總結道。
但一些專家認為，現在說疫苗提供如此高水平的保護還為時過早——尤其是只注射一劑疫苗——而且最近的其他報告顯示謹慎是有必要的。
以預印本形式發表的一項法國研究著眼於與已知患有猴痘的人有高風險接觸的人的暴露後疫苗接種。該分析包括 276 人，主要是男男性行為者，他們在 5 月 27 日至 7 月 13 日期間接受了單劑 MVA-BN，暴露後中位延遲為 11 天。其中，12 人（4%）感染了猴痘，但沒有一個是嚴重的。 12 人中有 10 人在接種疫苗後 5 天內出現猴痘，但有 2 人在接種疫苗後 22 天和 25 天出現突破性感染。巴黎 Hôpital Bichat 的 Michael Thy 博士及其同事總結說，疫苗接種策略「對猴痘具有良好的耐受性和有效性，但並不能完全預防突破性感染」。
來自芝加哥霍華德布朗健康中心（美國中西部最大的猴痘疫苗接種點）的 Aniruddha Hazra 博士及其同事分析了單劑 MVA-BN 後的感染情況。這項發表在 JAMA 上的研究包括 7,339 名在 6 月 28 日至 9 月 9 日期間接種了第一劑疫苗的人。在這組中，有 90 人感染了猴痘。這些病例中有四分之三以上（77%）發生在接種疫苗後的第一周（37 例）或第二週（32 例）。但有八人在第一次接種後一個多月後檢測出陽性，其中兩人在三週前接種了第二次。除 1 人外，其他人都患有輕度疾病，病灶少於 10 個。
在作為預印本發表的另一項研究中，鹿特丹伊拉斯姆斯大學醫學中心的 Luca Zaeck 博士及其同事比較了接種 MVA-BN 疫苗的人、接種了較老的天花疫苗的人以及猴痘檢測呈陽性的人的抗體反應。他們發現，與其他兩組相比，MVA-BN 接受者的中和抗體水平較低。僅接受一劑疫苗的人在接種疫苗後 4 周和 8 週「幾乎沒有產生抗體反應」。即使在第二劑之後抗體仍然相對較低，但第三劑提高了它們的水平。
研究人員總結說：「由於目前尚不清楚猴痘病毒中和抗體在預防疾病和傳播方面的作用，並且尚未確定對猴痘病毒感染的保護作用，這提出了一個問題，即接種疫苗的個體受到的保護程度如何」。
相比之下，巴伐利亞北歐的研究人員在另一份預印本中報告說，單次和雙次皮下注射 MVA-BN 誘導的持久中和抗體反應與舊天花疫苗所見的反應相當。抗體水平保持高水平至少六個月，但隨後在兩年內恢復到疫苗接種前的水平。然而，這並不意味著失去免疫力，因為 B 細胞和 T 細胞提供更持久的保護。
「在僅依靠疫苗接種來遏制猴痘爆發之前，還需要進行更多的研究」。
這項研究還發現，給以前接種過舊天花疫苗的人注射 MVA-BN 加強針會導致抗體迅速增加，達到比沒有事先接種疫苗的一劑或兩劑 MVA-BN 更高的水平。兩年後，當接受一到兩次初始劑量的 MVA-BN 的人被給予加強劑時，也可以看到快速的抗體反應，這顯示加強劑激活了現有的記憶 B 細胞。
鑑於迄今為止的混合證據，專家警告說，接種疫苗的人可能仍然處於危險之中，在僅依靠疫苗接種來遏制猴痘爆發之前，還需要進行更多的研究。雖然 MVA-BN 疫苗確實提供了一定的免疫力，但它並不能完全預防感染，尤其是在僅注射一劑之後。事實上，一些證據顯示可能需要第三次加強劑量才能獲得最佳保護。
康奈爾大流行預防和應對中心的傑伊·瓦爾馬博士告訴 MedPage Today：「公共衛生官員必須努力向接種疫苗的人傳達這種不確定性，這一點絕對至關重要」。 Walensky 和 Hazra 都認為持續降低風險很重要，特別是在第二劑疫苗之前和疫苗接種後的兩週內。
Monkeypox vaccine appears effective, but studies have mixed results
Liz Highleyman / 13 October 2022 / aidsmap
New Africa/Shutterstock.com
The MVA-BN smallpox and monkeypox vaccine, sold as Imvanex in Europe and Jynneos in the United States, has now been widely rolled out in several countries, but questions remain about its effectiveness in real-world use.
A recent US analysis suggests that men who received the vaccine were about 14 times less likely to develop monkeypox, but experts say more research is needed before relying on vaccination alone to curb the monkeypox outbreak.
The ongoing monkeypox outbreak in non-endemic countries has slowed dramatically in Europe and the US after peaking in late summer. As of 10 October, the UK Health Security Agency (UKHSA) has identified 3673 confirmed or probable cases, including 121 reported in the previous month. As of 12 October, the US Centers for Disease Control and Prevention (CDC) has tallied 27,022 cases in the US and more than 72,400 cases worldwide. Five months into the outbreak, monkeypox still overwhelmingly affects men who have sex with men.
The UK, which saw the first cases of this outbreak in May, was among the first to report that it had turned a corner. In late August, the World Health Organization reported that new cases had fallen by 21% worldwide. But some areas, including Latin America, continue to see high numbers of new cases.
Health officials and advocates attribute the decline to multiple factors, including natural immunity after infection, vaccination and behaviour change. A recent CDC survey found that about half of gay, bisexual and other men who have sex with men said they had made changes such as having fewer sex partners. The latest UKHSA technical report notes that two STIs, Shigella and lymphogranuloma venereum, have also declined, confirming behaviour change.
But the real-world effectiveness of the monkeypox vaccine has not yet been determined.
Bavarian Nordic’s MVA-BN vaccine, which uses a weakened strain of vaccinia virus, was developed as a safer alternative to the live-virus ACAM2000 smallpox vaccine. Monkeypox is related to smallpox, and the same vaccines can be used for both. Routine smallpox vaccination was discontinued after the disease was eradicated in 1980, which has facilitated the spread of monkeypox. Because monkeypox virus has a long incubation period, vaccines can be used both as post-exposure prophylaxis for up to two weeks after exposure and as pre-exposure prophylaxis for people at risk.
MVA-BN was authorised as a two-dose series administered by subcutaneous injection a month apart. In an effort to stretch the limited vaccine supply, some countries have switched to intradermal administration under the upper layer of skin, which allows a single vial to be split into five doses. A study in 2015 showed that antibody responses were similar with subcutaneous or intradermal injection, and a new clinical trial sponsored by the US National Institutes of Health will see if the vial could be split further, into ten doses. Regardless of the administration method, participants will have a second dose one month after their first.
MVA-BN was tested against monkeypox in non-human primates. While it reduced the likelihood of symptomatic illness and death, it did not reliably prevent infection. Prior to this outbreak, however, research in humans was limited to immunogenicity studies that looked at antibody levels after vaccination.
For example, in a phase III trial published in 2019, people randomly assigned to receive MVA-BN or ACAM2000 had comparable antibody responses. Research in the Democratic Republic of Congo in the 1980s found that people who had received a smallpox vaccine before it was discontinued were 85% less likely to contract monkeypox. Because MVA-BN produces comparable immune responses, it was assumed that it would provide similar protection. But some cases in the current outbreak have occurred among people who previously had smallpox jabs. MVA-BN has not been tested in Nigeria despite an ongoing monkeypox outbreak there since 2017. A vaccine trial for at-risk healthcare workers in the Democratic Republic of Congo is underway, but results have not yet been reported.
MVA-BN is safer and better tolerated than older replicating virus smallpox vaccines, which can cause severe side effects and produce a lesion that sheds live virus. Older vaccines are not considered safe for immunocompromised people, pregnant women, people with skin conditions or people with HIV. In contrast, the most common side effect of MVA-BN is mild injection site reactions. Intradermal administration can cause more itching and redness.
Several questions about MVA-BN remain to be answered. It is not known how long protection will last, though vaccination or prior monkeypox infection are thought to confer long-term immunity. Historically, monkeypox was typically transmitted between members of the same household or via contact with animals; it is not known how well the vaccine protects against sexual transmission. A 2015 study found that HIV-positive people with adequate CD4 counts respond well to MVA-BN, but little is known about responses in people with low CD4 counts.
Studies in the current outbreak
In an effort to learn more about real-world effectiveness, CDC researchers analysed outcomes among men who were eligible for monkeypox vaccination. The study, published in the CDC’s Morbidity and Mortality Weekly Report, was based on 5402 monkeypox cases that occurred between 31 July and 3 September, a period when the vaccine was widely available in the US but most people had only received their first dose.
Preliminary results suggest that men who received a single vaccine dose at least two weeks prior were 14 times less likely to contract monkeypox than eligible men who were not vaccinated, CDC director Dr. Rochelle Walensky told reports at a recent media briefing. But this analysis was not able to control for confounding factors. For example, men who were early vaccine adopters might have also changed their sexual behaviour.
“This early finding suggests that a single dose of Jynneos vaccine provides some protection against monkeypox infection,” the study authors wrote. “The degree and durability of such protection is unknown, and it is recommended that people who are eligible for monkeypox vaccination receive the complete two-dose series.”
“While the vaccine certainly provides some immunity, it does not prevent infection entirely, especially after just one dose.”
A smaller Israeli study, published as a pre-print, looked at outcomes among 1970 vaccine-eligible men who either were on HIV PrEP or were HIV-positive and had a recent STI. Of these, 873 received one dose of the MVA-BN vaccine between 31 July and 18 August and had at least 25 days of follow-up. Three vaccinated and 15 unvaccinated men contracted monkeypox. This works out to a vaccine effectiveness estimate of 79%, though the number of cases was small and the confidence interval is wide (ranging from 24% to 94%). “Our results suggest that a single dose of MVA is associated with a significantly lower risk for monkeypox virus infection in high-risk individuals,” the researchers concluded.
But some experts think it’s premature to say the vaccine provides such a high level of protection – especially with only one dose — and other recent reports suggest caution is warranted.
A French study, published as a pre-print, looked at post-exposure vaccination of people who had high-risk contact with a person known to have monkeypox. The analysis included 276 individuals, mostly men who have sex with men, who received a single dose of MVA-BN between 27 May and 13 July with a median delay of 11 days after exposure. Of these, 12 (4%) contracted monkeypox, but none of the cases was severe. Ten of the 12 developed monkeypox within five days after vaccination, but two had breakthrough infections at 22 and 25 days post-vaccination. The vaccination strategy “was well tolerated and effective against monkeypox but did not completely prevent breakthrough infections,” Dr Michael Thy of Hôpital Bichat in Paris and colleagues concluded.
Dr Aniruddha Hazra and colleagues from Howard Brown Health in Chicago — the largest monkeypox vaccination site in the US Midwest — analysed infections after a single dose of MVA-BN. The study, published in JAMA, included 7339 people who received their first vaccine dose between 28 June and 9 September. Of this group, 90 contracted monkeypox. More than three quarters of these cases (77%) occurred during the first week (37 cases) or second week (32 cases) after vaccination. But eight people tested positive more than a month after their first dose, including two who had had their second dose more than three weeks earlier. All but one had mild illness with fewer than 10 lesions.
In another study published as a pre-print, Dr Luca Zaeck of Erasmus University Medical Centre in Rotterdam and colleagues compared antibody responses in people who received the MVA-BN vaccine, those who received an older smallpox vaccine and those who tested positive for monkeypox. They found that MVA-BN recipients had low levels of neutralising antibodies compared with the other two groups. People who received just one dose “hardly developed antibody responses” at four and eight weeks post-vaccination. Antibodies remained relatively low even after the second dose, but a third dose boosted their levels.
“As the role of monkeypox virus neutralising antibodies for protection against disease and transmissibility is currently unclear and no correlate of protection against monkeypox virus infection has been identified yet, this raises the question how well vaccinated individuals are protected,” the researchers concluded.
In contrast, researchers at Bavarian Nordic reported in another pre-print that single and double subcutaneous doses of MVA-BN induced durable neutralising antibody responses comparable to those seen with older smallpox vaccines. Antibody levels remained high for at least six months but then returned to pre-vaccine levels by two years. However, this does not mean immunity was lost, as B-cells and T-cells provide longer-lasting protection.
“More research is needed before relying on vaccination alone to curb the monkeypox outbreak.”
This study also found that a MVA-BN booster jab given to people who previously received an older smallpox vaccine induced a rapid increase in antibodies, reaching higher levels than one or two doses of MVA-BN without prior vaccination. A rapid antibody response was also seen when people who received one or two initial doses of MVA-BN were given a booster two years later, suggesting the booster activates existing memory B-cells.
Given the mixed evidence to date, experts caution that vaccinated people may still be at risk, and more research is needed before relying on vaccination alone to curb the monkeypox outbreak. While the MVA-BN vaccine certainly provides some immunity, it does not prevent infection entirely, especially after just one dose. Indeed, some evidence suggests a third booster dose may be needed for optimal protection.
“It is absolutely critical that public health officials work on messaging this uncertainty to people being vaccinated,” Dr Jay Varma of the Cornell Center for Pandemic Prevention and Response told MedPage Today. Both Walensky and Hazra suggested that continued risk reduction is important, particularly before the second dose and for two weeks after vaccination.
References
Payne Ab et al. Incidence of Monkeypox Among Unvaccinated Persons Compared with Persons Receiving ≥1 JYNNEOS Vaccine Dose — 32 U.S. Jurisdictions, July 31–September 3, 2022. Morbidity and Mortality Weekly Report, 7 October 2022 (open access).
DOI: http://dx.doi.org/10.15585/mmwr.mm7140e3.
Arbel R et al. Effectiveness of a single-dose Modified Vaccinia Ankara in Human Monkeypox: an observational study. Research Square pre-print, 23 September 2022 (open access).
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Thy M et al. Breakthrough infections after post-exposure vaccination against monkeypox. medRxiv pre-print, 4 August 2022 (open access).
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Hazra A et al. Human Monkeypox Virus Infection in the Immediate Period After Receiving Modified Vaccinia Ankara Vaccine. JAMA, published online 30 September 2022.
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Zaeck LM et al. Low levels of monkeypox virus neutralizing antibodies after MVA-BN vaccination in healthy individuals. medRxiv pre-print, 1 September 2022 (open access).
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Ilchmann H et al. Single and 2-dose vaccinations with MVA-BN induce durable B cell memory responses in healthy volunteers that are comparable to older generation replicating smallpox vaccines. medRxiv pre-print, 9 September 2022 (open access).
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