Antibody responses to the RTS,S/AS01E vaccine and Plasmodium falciparum antigens after a booster dose within the phase 3 trial in Mozambique

The RTS,S/AS01E vaccine has shown consistent but partial vaccine efficacy in a pediatric phase 3 26 clinical trial using a 3-dose immunization schedule. A fourth dose 18 months after the primary 27 vaccination was shown to restore the waning efficacy. However, only total IgG against the 28 immunodominant malaria vaccine epitope has been analyzed following the booster. To better 29 characterize the magnitude, nature and longevity of the immune response to the booster, we 30 measured levels of total IgM, IgG and IgG1-4 subclasses against three constructs of the 31 circumsporozoite protein (CSP) and the hepatitis B surface antigen (HBsAg, also present in RTS,S) 32 by quantitative suspension array technology in 50 subjects in the phase 3 trial in Manhiça, 33 Mozambique. To explore the impact of vaccination on naturally acquired immune responses, we 34 measured antibodies to P. falciparum antigens not included in RTS,S. We found increased IgG, 35 IgG1, IgG3 and IgG4, but not IgG2 nor IgM, levels against vaccine antigens one month after the 4th 36 dose. Overall, antibody responses to the booster dose were lower than the initial peak 37 response to primary immunization and children had higher IgG and IgG1 levels than infants. 38 Higher anti-Rh5 IgG and IgG1-4 levels were detected after the booster dose, suggesting that RTS,S 39 partial protection could increase some blood stage antibody responses. Our work shows that the 40 response to the RTS,S/AS01E booster dose is different from the primary vaccine immune 41 response and highlights the dynamic changes in subclass antibody patterns upon the vaccine 42 booster and with acquisition of adaptive immunity to malaria.

RTS,S/AS01E疫苗在采用3剂次免疫程序的儿科三期临床试验中展现出稳定但部分有效的保护效力。在基础免疫接种18个月后追加第4剂加强针，可恢复衰减的疫苗保护效力。但目前仅针对该免疫显性疟疾疫苗表位的总IgG开展了加强针接种后的免疫分析。为更精准地表征加强针免疫应答的强度、性质与持久性，我们采用定量悬浮阵列技术（quantitative suspension array technology），对莫桑比克马希卡地区的50名三期临床试验受试者体内针对3种环子孢子蛋白（circumsporozoite protein, CSP）构建体以及乙型肝炎表面抗原（hepatitis B surface antigen, HBsAg，亦存在于RTS,S疫苗中）的总IgM、总IgG及IgG1-4亚类抗体水平进行了检测。为探究疫苗接种对自然获得性免疫应答的影响，我们还检测了RTS,S疫苗未覆盖的恶性疟原虫（P. falciparum）抗原对应的抗体水平。研究发现，第4剂加强针接种1个月后，受试者体内针对疫苗抗原的IgG、IgG1、IgG3及IgG4水平显著升高，而IgG2与IgM水平未出现明显变化。整体而言，加强针诱导的抗体应答水平低于基础免疫的初始峰值应答，且儿童受试者的IgG与IgG1水平显著高于婴幼儿受试者。加强针接种后，受试者体内的抗Rh5 IgG及IgG1-4抗体水平也显著升高，提示RTS,S的部分保护作用可能增强了部分疟原虫红内期抗体应答。本研究证实，针对RTS,S/AS01E加强针的免疫应答与基础疫苗免疫应答存在显著差异，并凸显了加强针接种以及机体获得疟疾适应性免疫后，抗体亚类模式所发生的动态变化。