孩童每年的流感疫苗接種會影響對流行病毒株的免疫力嗎？

作者：Laurie Barclay, MD  
出處：WebMD醫學新聞

　　October 29, 2009 — 即將於12月印行的The Lancet Infectious Diseases期刊，在10月30日線上版中，一篇回應與反應文章發表的個人論點，指出對於孩童每年接種的季節性流感疫苗是否會停止對流行之病毒株產生免疫力的論辯。
　　
　　荷蘭路特丹Erasmus醫學中心的Rogier Bodewes、Joost H.C.M. Kreijtz、Guus F. Rimmelzwaan等人寫道，每年的疫苗接種是必須的，因為流感病毒會有抗原飄移而需要每年更新疫苗，受到抗體是由自然感染或接種疫苗引起的選擇性壓力。
　　
　　作者們表示，包括美國和一些歐洲國家，已經有許多國家建議對6至59個月大健康孩童接種季節性流感疫苗，因為這個疾病是造成此一年齡層生病和住院的一個重要原因。雖然每年接種季節性流感對於包括孩童在內的所有高風險病患有幫助，但每年對6至59個月孩童施打季節性流感疫苗可能有一些未曾被深思的缺點。
　　
　　之前的研究多數是老鼠或其他動物研究，顯示感染A型流感病毒會引起異次型態免疫，對於A型流感病毒或其他無關的亞型有免疫力；雖然異次型態免疫不會有完整保護力，但是可以限制病毒複製與減少宿主的流感症狀和死亡率。
　　
　　作者們指出，當出現新的A型流感亞型時，應考慮人類之異次型態免疫的差異。有關的例子包括引起目前流感大流行的新型A型H1N1病毒，與增加人類感染數且會致命的高病原性禽流感H5N1病毒。
　　
　　作者們認為，使用疫苗以預防季節性流感病毒感染，可能反而會使得無法誘導對大流行病毒株的異次型態免疫。嬰兒和其他未具有抗體的人將會有極高風險發生此狀況。
　　
　　為了檢驗他們的理論，作者們建議，應密切監控自出生後即每年接受季節性流感疫苗之嬰兒的住院率與死亡率，並且和沒有接受疫苗、年齡相仿的孩童進行比較。目前的H1N1大流行提供一個絕佳的機會來研究異次型態免疫，以確認每年流感疫苗的潛在傷害。
　　
　　同時，作者們支持目前的H1N1流感疫苗計畫，認同這可以降低各年齡層的發病率與死亡率。
　　
　　研究作者結論表示，使用這些大流行流感疫苗將推翻與每年季節性流感疫苗有關的理論議題。發展與使用可引起廣泛免疫保護力的疫苗，或許是這些潛在問題的解決之道，我們認為這是首要之務。
　　
　　反應與回應中，芬蘭Turku大學醫院的Terho Heikkinen醫師與Ville Peltola醫師，認為季節性流感疫苗對孩童的預防效果，遠超過無法誘導發生對大流行病毒株之異次型態免疫的理論風險。不過，他們同意Bodewes醫師等人的是，需要可誘導更廣泛免疫反應的有效流感疫苗。
　　
　　Heikkinen醫師與Peltola醫師寫道，動物實驗的結果一定無法直接推論到人類，更別說要成為任何疫苗政策的基礎。有足夠證據證明幼童的流感大爆發，且在每個流感季節都會發生。相對的，沒有臨床證據認為接種流感疫苗的孩童將無法誘導產生異次型態免疫，而因此對小孩有長期不利。
　　
　　Heikkinen醫師與Peltola醫師因此提議繼續現行的流感疫苗計畫。
　　
　　他們結論表示，在等待改善流感疫苗時，單純的問題是，我們應否只因理論上認為停止疫苗在未來可以有比較不嚴重疾病的可能性，讓幼童遭受嚴重且可能致命但卻可以簡單預防的疾病？我們相信，這個問題的答案很簡單。
　　
　　Rimmelzwaan醫師是Viroclinics BV的顧問。其他兩位發表個人觀點的作者宣告沒有相關財務關係。Heikkinen 醫師為Novartis、 Medimmune、GlaxoSmithKline和 Solvay藥廠提供諮詢服務。Peltola醫師接受GlaxoSmithKline藥廠的資金且為Novartis藥廠提供諮詢服務。
　　
　　Lancet Infect Dis. 線上發表於2009年10月30日。

Do Yearly Influenza Vaccinations for Children Affect Immunity Against Pandemic Strains?

By Laurie Barclay, MD
Medscape Medical News

October 29, 2009 — Whether yearly vaccinations for children against seasonal influenza might stop immunity developing against pandemic strains is debated in a personal view and reflection and reaction published online October 30 and will appear in the December print edition of The Lancet Infectious Diseases.

"Yearly vaccination is necessary because of the substantial antigenic drift of influenza viruses that necessitates the update of vaccines every year...driven by selective pressure mediated by antibodies induced by natural infection or vaccination," write Rogier Bodewes, DVM; Joost H.C.M. Kreijtz, PhD; and Guus F. Rimmelzwaan, PhD, from Erasmus Medical Center in Rotterdam, The Netherlands.

"The vaccination of healthy children aged 6–59 months against seasonal influenza has been recommended in several countries, including the USA and some European countries," the authors continue, "because the disease is an important cause of illness and admission to hospital in this age group. Although annual vaccination against seasonal influenza is beneficial for all patients at high risk, including children, vaccination of the 6–59 month age group every year against seasonal influenza might have a downside that has not been given much thought."

Previous studies, mostly in mice and other animals, have shown that infection with influenza A viruses can induce heterosubtypic immunity, which is protective immunity to influenza A viruses of other unrelated subtypes. Although heterosubtypic immunity does not offer full protection, it can limit virus replication and reduce influenza symptoms and mortality in the host.

The authors note that the ramifications of heterosubtypic immunity should be considered in humans when a new subtype of influenza A virus is introduced into the population. Pertinent examples include the novel influenza A H1N1 virus causing the present influenza pandemic and the highly pathogenic avian influenza H5N1 viruses responsible for increasing numbers of human infections, which are often fatal.

The authors suggest that an untoward effect of preventing infection with seasonal influenza viruses by vaccination might be to prevent the induction of heterosubtypic immunity to pandemic strains. Infants and other immunologically naive individuals would be at greatest risk were this to occur.

To test their theory, the authors suggest that hospitalizations and mortality rates among infants who have received yearly influenza vaccination since birth should be closely monitored and compared with those in age-matched children who were not vaccinated. The present H1N1 pandemic offers a unique opportunity to investigate heterosubtypic immunity and to determine potential harms of annual influenza vaccination.

In the meantime, the authors support the current vaccination program against H1N1 influenza and acknowledge that it will decrease morbidity and deaths in all age groups.

"Use of these pandemic influenza vaccines will override the theoretical issues associated with yearly vaccination against seasonal influenza," the study authors conclude. "The development and use of vaccines that can induce broad protective immunity might be a solution for these potential problems and we think this is a priority."

In an accompanying reflection and reaction, Terho Heikkinen, MD, and Ville Peltola, MD, from Turku University Hospital in Finland, argue that prevention of seasonal influenza in children by vaccination far outweighs the theoretical risk of preventing the induction of heterosubtypic immunity to pandemic strains. However, they agree with Dr. Bodewes and colleagues that more effective influenza vaccines that could induce broader immune responses are needed.

"The results of experimental animal studies can never be extrapolated directly to human beings, let alone form the basis of any vaccination policy," Dr. Heikkinen and Dr. Peltola write. "There is ample evidence for the great burden of influenza in young children, and this burden appears during every influenza season. By contrast, there is no clinical evidence that vaccinating children against influenza would prevent the induction of heterosubtypic immunity and thereby be disadvantageous to children in the long run."

Dr. Heikkinen and Dr. Peltola therefore advocate continuing the ongoing influenza vaccination program.

"While waiting for improved influenza vaccines, the simple question is should we let young children suffer from a severe and potentially lethal but easily preventable illness, just because there is a theoretical possibility that withholding vaccination might result in a slightly less severe illness sometime in the future?" they conclude. "We believe that the answer to this question is a simple one."

Dr. Rimmelzwaan is a consultant to Viroclinics BV. The other 2 personal view authors have disclosed no relevant financial relationships. Dr. Heikkinen has provided consultancy services to Novartis, Medimmune, GlaxoSmithKline, and Solvay. Dr. Peltola has received grants from GlaxoSmithKline and provided consultancy services to Novartis.

Lancet Infect Dis. Published online October 30, 2009.