Clinical Studies of Vaccines for Pandemic Influenza

H9n2冷适应(Ca)疫苗：一项第一阶段研究在50名住进病房的健康成年人中启动。该疫苗是安全的，耐受性良好，但复制水平很低。尽管疫苗病毒的脱落很小，但在接种两剂疫苗后，92%的血清阴性参与者的HI抗体滴度增加了4倍，79%的人中和抗体滴度增加了4倍；100%的人至少通过其中一种检测方法检测到了应答。因此，尽管复制受到高度限制，但两剂H9N2/AA CA疫苗对血清阴性的成年人具有免疫原性。 H5N1冷适应(Ca)疫苗：根据1997年、2003年和2004年分离的H5N1病毒开发了三种候选疫苗。在每种病毒中，HA和NA基因都来自野生型H5N1病毒。每种情况下的HA都被修饰，以去除作为毒力基序的多碱性氨基酸裂解位点。以A/越南/1203/2004(H5N1)病毒为基础的2004年H5N1疫苗的安全性、传染性和免疫原性的I阶段试验在20名18-49岁的健康成年人中进行，每剂6.7log10 TCID50。临床试验是在隔离病房进行的。受试者接种两剂疫苗，间隔28至62天，并在两剂疫苗接种后3周被隔离在隔离单元中。在这个剂量下，疫苗病毒的复制水平、传染性和免疫原性都很低。因此，开展了一项研究，以评估中等较高剂量(7.5log10 TCID50)同一疫苗的安全性、传染性和免疫原性。19名受试者接受了两次这种剂量的治疗。疫苗是安全的，耐受性良好。这项研究的数据分析正在进行中。 为了确定2004年H5N1 CA病毒的低传染性和低免疫原性是否是该毒株所特有的，对2003年H5N1 CA疫苗进行了I期研究。16名受试者接种了2剂2003年H5N1 CA疫苗。疫苗是安全的，耐受性良好。这项研究的数据分析正在进行中。 H7N3冷适应(Ca)疫苗：基于有希望的小鼠和雪貂临床前数据，进行了一项第一阶段研究，以评估以A/鸡/不列颠哥伦比亚省/CN-6/2004(H7N3)为基础的H7N3冷适应(Ca)疫苗的安全性、复制水平、传染性和免疫原性。17名受试者接种了两剂疫苗。该疫苗是安全的，总体上耐受性良好。这项研究的数据分析正在进行中。 H_2N_2冷适应(CA)疫苗：H_2N_2病毒引起了1957年的流感大流行，并在人类中传播，直到1968年被H3N_2病毒取代。虽然H2病毒自1968年以来就没有在人类身上传播过，但这一亚型在世界各地的禽类水库中仍然存在。H2疫苗是准备大流行的高度优先事项，因为H2病毒已被证明具有在人类身上致病的能力，而1968年后出生的人缺乏H2特异性免疫。由于目前在美国使用的获得许可的减毒活流感疫苗携带甲型流感病毒/AnnArbor/6/60(H2n2)ca病毒的内部蛋白基因，这种病毒自然是作为h2疫苗进行评估的首选。然而，这种具有H2 HA和N2NA的病毒尚未在血清阴性的人中进行评估。IND被提交进行I期研究，以评估A/Ann Arbor/6/60ca(H2N2)病毒的安全性、复制水平、传染性和免疫原性。这项研究正在进行中。 H6N1冷适应(Ca)疫苗：基于在小鼠和雪貂身上有希望的临床前数据，IND被提交进行第一阶段研究，以评估基于A/TEAL/Hong Kong/W312/1997(H6N1)的H6N1冷适应(Ca)疫苗的安全性、复制水平、传染性和免疫原性。这项研究将于2008年10月启动。

H9N2 cold-adapted (ca) vaccine: A Phase I study was initiated in 50 healthy adults who were admitted to an in-patient unit. The vaccine was safe and well tolerated but the level of replication was low. Although shedding of vaccine virus was minimal, 92% of seronegative participants had >4-fold rises in HI antibody titer and 79% had >4-fold rises in neutralizing antibody titer following two doses of vaccine; 100% had a response detected by at least one of these assays. Therefore, despite being highly restricted in replication, two doses of H9N2/AA ca vaccine were immunogenic in seronegative adults. H5N1 cold-adapted (ca) vaccines: Three candidate vaccines were developed based on H5N1 viruses isolated in 1997, 2003 and 2004. In each virus, the HA and NA genes were derived from wild-type H5N1 viruses. The HA in each case was modified to remove the multibasic amino acid cleavage site that is a virulence motif. A Phase I trial for safety, infectivity, and immunogenicity of the 2004 H5N1 Vaccine based on the A/VietNam/1203/2004 (H5N1) virus, was undertaken at a dose of 6.7 log10 TCID50 per dose in 20 healthy adults, aged 18-49 years. The clinical trial was conducted in an isolation unit. Subjects received two doses of vaccine, administered 28 to 62 days apart, and were sequestered in an isolation unit 3 weeks following both doses. The level of replication, infectivity, and immunogenicity of the vaccine virus at this dose was low. Therefore, a study was undertaken to evaluate the safety, infectivity and immunogenicity of a moderately higher dose (7.5 log10 TCID50) of the same vaccine. Nineteen subjects received two doses of this dose. The vaccine was safe & well tolerated. Analysis of data from this study is in progress. In order to determine whether the finding of low infectivity and low immunogenicity observed with the 2004 H5N1 ca virus was unique to this strain, a Phase I study was undertaken with the 2003 H5N1 ca vaccine. Sixteen subjects received 2 doses of the 2003 H5N1 ca vaccine. The vaccine was safe & well tolerated. Analysis of data from this study is in progress. H7N3 cold-adapted (ca) vaccine: Based on promising preclinical data in mice and ferrets, a Phase I study was undertaken to evaluate the safety, level of replication, infectivity and immunogenicity of an H7N3 ca vaccine based on A/chicken/British Columbia/CN-6/2004 (H7N3). Seventeen subjects received two doses of the vaccine. The vaccine was safe and generally well tolerated. Analysis of data from this study is in progress. H2N2 cold-adapted (ca) vaccine: H2N2 viruses caused the 1957 influenza pandemic and circulated in humans until 1968 when they were replaced by H3N2 viruses. Although H2 viruses have not circulated in humans since 1968, this subtype is maintained in avian reservoirs worldwide. An H2 vaccine is a high priority in preparing for a pandemic because H2 viruses have a proven capability for causing disease in humans and persons born after 1968 lack H2-specific immunity. Because the currently licensed live attenuated influenza vaccine utilized in the United States bears the internal protein genes of the influenza A/AnnArbor/6/60 (H2N2) ca virus, this virus was a logical first choice for evaluation as an H2 vaccine. However, this virus with the H2 HA and N2 NA has not been evaluated in seronegative people. An IND was submitted for a Phase I study to evaluate safety, level of replication, infectivity and immunogenicity of A/Ann Arbor/6/60 ca (H2N2) virus. This study is in progress. H6N1 cold-adapted (ca) vaccine: Based on promising preclinical data in mice and ferrets, an IND was submitted for a Phase I study to evaluate safety, level of replication, infectivity and immunogenicity of an H6N1 ca vaccine based on A/teal/Hong Kong/W312/1997 (H6N1). The study will be initiated in October 2008.