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根据3月14日出版的每周死亡率与发病率报告（Morbidity and Mortality Weekly Report）中的更新规范，预防接种谘询委员会(ACIP)不再偏好使用麻疹、腮腺炎、德国麻疹、水痘(MMRV)混合疫苗。
Kaiser Permanente疫苗研究中心、疫苗安全资料连结快速反应分析小组的N.P. Klein医师等人写道，在2008年2月27日，疫苗实务谘询委员会发布了新讯息，关于12至23个月大的小孩接种麻疹、腮腺炎、德国麻疹、水痘混合疫苗(ProQuad?, Merck & Co.,药厂、Whitehouse Station、纽泽西) 之后出现热抽搐的风险；此报告总结目前使用MMRV疫苗之后发生热抽搐风险的知识，并且发表ACIP在这些新讯息公布之后所更新的建议，这些更新的建议改变了ACIP之前偏好使用MMRV混合疫苗，而非分别注射等效价的MMR疫苗加上水痘疫苗的立场。
2005年9月6日，美国食品药物管理局(FDA)核准四合一的MMRV混合疫苗用于12个月至12岁的小孩；为了预防麻疹、腮腺炎、德国麻疹、水痘，MMRV疫苗用于取代三合一的MMR治疗加上水痘疫苗；为了符合建议施打两次的疫苗政策，第一剂建议在12至15个月大，第二剂在4至6岁。
根据核准上市之前的研究，相较于给予MMR加上水痘疫苗者，MMRV混合疫苗在第一剂之后0至42天发烧5至12度的机率较高；MMRV混合疫苗可能增加热抽搐风险的顾虑促使美国疾病管制预防中心(CDC)和Merck药厂进行上市后研究。
根据疫苗安全资料连结(VSD)的资料，该资料系统常规使用病患资料进行疫苗安全性之监控，对于12至23个月大的小孩，和MMR疫苗(许多小孩也同时接种水痘疫苗)相比，MMRV 疫苗的抽搐风险增加；接受MMRV疫苗者和同一天接种MMR疫苗加上水痘疫苗相比，两组在注射之后7至10天发生抽处的比率都明显增加。
后续的VSD 研究比较了接种MMRV疫苗的43,353名年纪在12至23个月的小孩，以及同一天接种MMR疫苗加上水痘疫苗的314,599名年纪在12至23个月的小孩，在接种疫苗之后7至10天的热抽搐风险；初步发现显示，接种MMRV疫苗组的热抽搐发生率为10,000分之9，接种MMR疫苗加上水痘疫苗者为10,000分之4 (校正风险比 [OR] = 2.3; 95% 信心区间[CI] = 1.6 – 3.2; P < .0001)。
根据这些发现，相较于同一天接种MMR疫苗加上水痘疫苗者，在接种疫苗之后7至10天，每2,000名接种MMRV 疫苗的小孩会比前组多一人发生热抽搐；在接种疫苗之后发生热抽搐的166人之中，26 人(16%)住院；无人死亡。
Merck药厂进行之核准后研究的暂时性分析显示，接种MMRV疫苗5至12天确认发生热抽搐的相对风险(RR)比对照控制组高出2.3倍 (95% CI, 0.6 – 9.0)；虽然RR没有统计上的显著意义，但相似于VSD研究所指的接种疫苗之后7至10天的OR。
至于评估在4至6岁给予第二剂MMRV疫苗之后的热抽搐风险，不论是VSD研究或者是Merck 的研究，4至6岁时的热抽搐风险都比12至15个月时低，而之前的研究显示第二剂的MMRV疫苗比较不会引起发烧。
规范的作者写道，热抽搐在小孩并不常见，且一般预后良好，不过，这种情况往往会给父母亲以及家中成员带来压力；热抽搐可能发生在一些疫苗施打之后，但很罕见；MMR疫苗之前曾有报告指出在接种后8至14天发生热抽搐；相较于在过去30天未曾接种疫苗者，每3,000至4,000名接种MMR的小孩会有一人发生热抽搐。
2007年，ACIP建议之水痘预防和ACIP一般疫苗建议提出，偏好使用MMRV混合疫苗而非分开注射等效价的MMR疫苗加上水痘疫苗。
根据VSD和Merck研究结果所指出的第一剂MMRV疫苗接种之后增加热抽搐风险的基础，ACIP在2008年2月27日的会议中投票，改变了前述关于MMRV疫苗的立场；此立场改变有考量到麻疹、腮腺炎、德国麻疹、水痘等疫苗的供应，也未曾限制MMRV疫苗，因为此一规范改变与疫苗的安全性和有效性无关。
更新的ACIP 建议如下：“混合MMRV疫苗核准用于12个月至12岁的健康小孩， MMRV疫苗使用于麻疹、腮腺炎、德国麻疹、水痘之免疫；ACIP对MMRV疫苗或者分别注射等效价的MMR疫苗加上水痘疫苗无偏好” 。
ACIP也提议，召集一个工作小组对接种第一剂MMRV疫苗之后发生热抽搐的风险进行深度分析；根据这些发现和其他资讯，CDC、 FDA和 ACIP 将考量未来的政策选项，沟通更新规范、采取必要的行动。
必须向疫苗不良反应通报系统(VAERS)通报接种疫苗之后的临床不良反应事件，可以上网http://www.vaers.hhs.gov 或者打电话 800-822-7967。
MMWR 每周死亡率与发病率报告. 2008;57(10):258–260.
Guidelines Updated for Administration of Combination MMRV Vaccine
By Laurie Barclay, MD
Medscape Medical News
The Advisory Committee on Immunization Practices (ACIP) no longer prefers administering combination measles, mumps, rubella, and varicella (MMRV) vaccine over separate injections of equivalent component vaccines, according to updated guidelines published in the March 14 issue of the Morbidity and Mortality Weekly Report.
"On February 27, 2008, new information was presented to the Advisory Committee on Immunization Practices...regarding the risk for febrile seizures among children aged 12 – 23 months after administration of the combination measles, mumps, rubella, and varicella...vaccine (ProQuadR, Merck & Co., Inc., Whitehouse Station, New Jersey)," write N.P. Klein, MD, PhD, from the Kaiser Permanente Vaccine Study Center, Oakland, California, and Vaccine Safety Datalink Rapid Cycle Analysis Team, and colleagues. "This report summarizes current knowledge regarding the risk for febrile seizures after MMRV vaccination and presents updated ACIP recommendations that were issued after presentation of the new information. These updated recommendations remove ACIP's previous preference for administering combination MMRV vaccine over separate injections of equivalent component vaccines (i.e., vaccine and varicella vaccine)."
On September 6, 2005, the US Food and Drug Administration (FDA) licensed the combination tetravalent MMRV vaccine for use in children aged 12 months to 12 years. To prevent measles, mumps, rubella, and varicella, MMRV vaccine can be used instead of trivalent MMR vaccine and monovalent varicella vaccine. To fulfill the recommended 2-dose vaccine policies, the first dose is recommended at age 12 to 15 months and the second at age 4 to 6 years.
Compared with administration of MMR vaccine and varicella vaccine at the same visit, MMRV vaccine was associated with a higher incidence of fever 5 to 12 and 0 to 42 days after the first vaccine dose, based on prelicensure studies. Concern regarding possible increased risk for febrile seizures potentially associated with MMRV vaccination led the Centers for Disease Control and Prevention (CDC) and Merck to conduct postlicensure studies.
According to data from the Vaccine Safety Datalink (VSD), which routinely monitors vaccine safety using computerized patient data, there was increased risk for seizures of any etiology in children aged 12 to 23 months who received MMRV vaccine vs MMR vaccine (many children also received varicella vaccine). When children given MMRV vaccine were compared with those given both MMR vaccine and a separate varicella vaccine at the same visit, both groups had statistically significant clustering of seizures 7 to 10 days after vaccination.
A subsequent VSD study compared the risk for febrile seizures 7 to 10 days after vaccination in 43,353 children aged 12 to 23 months who received MMRV vaccine vs 314,599 children aged 12 to 23 months who received MMR vaccine and varicella vaccine at the same visit. Preliminary findings show a rate of febrile seizures of 9 per 10,000 vaccinations among children who received MMRV vaccine vs 4 per 10,000 vaccinations in those who received MMR vaccine and varicella vaccine (adjusted odds ratio [OR] = 2.3; 95% confidence interval [CI] = 1.6 – 3.2; P < .0001).
On the basis of these findings, about 1 additional febrile seizure would occur in the 7- to 10-day postvaccination period among every 2000 children vaccinated with MMRV vaccine compared with children vaccinated with MMR vaccine and separate varicella vaccine given at the same visit. Of 166 children who had febrile seizures after vaccination, 26 (16%) were hospitalized; none died.
An interim analysis of an ongoing postlicensure study being conducted by Merck showed a 2.3-fold (95% CI, 0.6 – 9.0) higher relative risk (RR) for confirmed febrile seizures 5 to 12 days after MMRV vaccination compared with a matched control group. Although the RR was not statistically significant, it was similar to the OR reported by the VSD study for the period 7 to 10 days after vaccination.
Neither the VSD study nor the Merck study evaluated the risk for febrile seizures after MMRV vaccine given as a second dose at age 4 to 6 years, but rates of febrile seizure are typically lower at 4 to 6 years than at 12 to 15 months, and previous studies have shown that the second dose of MMRV vaccine is less likely to cause fever than the first dose.
"Febrile seizures are not uncommon in young children and generally have an excellent prognosis, although they often are distressing to parents and other family members," the guidelines authors write. "Febrile seizures can occur after certain vaccinations, although rarely. MMR vaccination has been associated previously with febrile seizures occurring 8 – 14 days later; approximately one additional febrile seizure occurs among every 3,000 – 4,000 children vaccinated with MMR vaccine, compared with children not vaccinated during the preceding 30 days."
The 2007 ACIP recommendations for prevention of varicella were consistent with ACIP General Recommendations on Immunization in that they included a preference for use of combination MMRV vaccine over separate injections of equivalent component vaccines (MMR vaccine and varicella vaccine).
On the basis of the VSD and Merck studies suggesting an elevated risk for febrile seizures after the first MMRV vaccine dose, ACIP voted at its February 27, 2008, meeting to change the preference language for MMRV vaccine. This change took into account the availability of alternative options for vaccination against measles, mumps, rubella, and varicella and the limited supply of MMRV vaccine because of manufacturing constraints unrelated to vaccine safety or efficacy.
The updated ACIP recommendation now reads as follows: "Combination MMRV vaccine is approved for use among healthy children aged 12 months – 12 years. MMRV vaccine is indicated for simultaneous vaccination against measles, mumps, rubella, and varicella. ACIP does not express a preference for use of MMRV vaccine over separate injections of equivalent component vaccines (i.e., MMR vaccine and varicella vaccine)."
The ACIP also advocated that a work group be convened for in-depth analysis of data regarding the increased risk for febrile seizures after the first dose of MMRV vaccine. On the basis of these findings and other information that becomes available, the CDC, FDA, and ACIP will consider future policy options, communicate updates, and implement further necessary actions.
The Vaccine Adverse Event Reporting System (VAERS) should be notified of clinically significant adverse events following vaccination online at http://www.vaers.hhs.gov or by telephone at 800-822-7967.
MMWR Morb Mortal Wkly Rep. 2008;57(10):258–260.