Clinical Studies of Vaccines for Pandemic Influenza

H9 N2冷适应（ca）疫苗：在50名住院的健康成年人中启动了一项I期研究。 该疫苗安全且耐受性良好，但复制水平较低。 尽管疫苗病毒的脱落是最小的，但在两剂疫苗后，92%的血清阴性参与者的HI抗体滴度增加>4倍，79%的中和抗体滴度增加>4倍; 100%的参与者通过这些测定中的至少一种检测到应答。因此，尽管在复制方面受到高度限制，但两剂H9 N2/AA ca疫苗在血清阴性成人中具有免疫原性。 H5 N1冷适应（ca）疫苗：根据1997年、2003年和2004年分离的H5 N1病毒开发了三种候选疫苗。在每种病毒中，HA和NA基因均来源于野生型H5 N1病毒。在每种情况下，HA被修饰以去除作为毒力基序的多碱基氨基酸切割位点。在20名18-49岁的健康成人中进行了基于A/Vietnam/1203/2004（H5 N1）病毒的2004 H5 N1疫苗的安全性、感染性和免疫原性的I期试验，剂量为6.7 log 10 TCID 50/剂。该临床试验在隔离病房进行。 受试者接受两剂疫苗，间隔28至62天接种，并在两剂疫苗接种后3周隔离在隔离单元中。在该剂量下，疫苗病毒的复制、感染性和免疫原性水平较低。因此，进行了一项研究，以评价中等较高剂量（7.5 log 10 TCID 50）相同疫苗的安全性、感染性和免疫原性。19例受试者接受了两次该剂量。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。 为了确定在2004年H5 N1 ca病毒中观察到的低感染性和低免疫原性的发现是否是该毒株特有的，对2003年H5 N1 ca疫苗进行了I期研究。16名受试者接种了2剂2003年H5 N1 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。 H7 N3冷适应（ca）疫苗：基于小鼠和雪貂中有希望的临床前数据，进行了一项I期研究，以评估基于A/鸡/不列颠哥伦比亚省/CN-6/2004（H7 N3）的H7 N3 ca疫苗的安全性、复制水平、感染性和免疫原性。17名受试者接种了两剂疫苗。该疫苗是安全的，一般耐受性良好。这项研究的数据分析正在进行中。 H2 N2冷适应（ca）疫苗：H2 N2病毒引起1957年流感大流行，并在人类中传播，直到1968年被H3 N2病毒取代。虽然H2病毒自1968年以来没有在人类中传播，但这种亚型在全世界的禽类宿主中保持。H2疫苗是预防大流行的高度优先事项，因为H2病毒已被证明具有在人类中引起疾病的能力，而1968年以后出生的人缺乏H2特异性免疫力。由于目前在美国使用的许可减毒活流感疫苗携带甲型流感/AnnArbor/6/60（H2 N2）ca病毒的内部蛋白基因，因此该病毒是评价H2疫苗的合理首选。然而，这种病毒与H2 HA和N2 NA尚未在血清阴性的人进行评估。提交了一份IND，用于I期研究，以评价A/安阿伯/6/60 ca（H2 N2）病毒的安全性、复制水平、感染性和免疫原性。这项研究正在进行中。 H6 N1冷适应（ca）疫苗：基于小鼠和雪貂中有希望的临床前数据，提交了一项IND进行I期研究，以评估基于A/teal/Hong Kong/W312/1997（H6 N1）的H6 N1 ca疫苗的安全性、复制水平、感染性和免疫原性。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.