Heterologous Protection against Malaria after Immunization with Plasmodium falciparum Sporozoites

BackgroundSterile protection in >90% of volunteers against homologous Plasmodium falciparum infection has been achieved only using the controlled human malaria infection (CHMI) model. This efficient model involves whole parasite immunizations under chloroquine prophylaxis (CPS-immunization), requiring only 30–45 mosquitoes bites infected with P. falciparum-sporozoites. Given the large diversity of P. falciparum parasites, it is essential to assess protection against heterologous parasite strains.MethodsIn an open-label follow-up study, 16 volunteers previously CPS-immunized and challenged with P. falciparum NF54 (West-Africa) in a dose de-escalation and challenge trial were re-challenged with clone NF135.C10 (Cambodia) at 14 months after the last immunization (NCT01660854).ResultsTwo out of thirteen NF54 protected volunteers previously fully protected against NF54 were also fully protected against NF135.C10, while 11/13 showed a delayed patency (median prepatent period of 10.5 days (range 9.0–15.5) versus 8.5 days in 5 malaria-naïve controls (p = 0.0005). Analysis of patency by qPCR indicated a 91 to >99% estimated reduction of liver parasite load in 7/11 partially protected subjects. Three volunteers previously not protected against NF54, were also not protected against NF135.C10.ConclusionThis study shows that CPS-immunization can induce heterologous protection for a period of more than one year, which is a further impetus for clinical development of whole parasite vaccines.Trial RegistrationClinicaltrials.gov NCT01660854背景：仅通过受控人体疟疾感染模型（controlled human malaria infection, CHMI），方可在超过90%的志愿者中实现针对同源恶性疟原虫感染的完全保护性免疫（无菌性保护）。该高效模型采用氯喹预防性给药条件下的全寄生虫免疫方案（CPS免疫，CPS-immunization），仅需30~45次携带恶性疟原子孢子的蚊虫叮咬即可完成。鉴于恶性疟原虫存在高度多样性，评估其针对异源寄生虫虫株的保护效果至关重要。 方法：本研究为开放标签随访研究，纳入16名既往接受CPS免疫，并在剂量递减攻击试验中接受恶性疟原虫NF54（西非株）攻击的志愿者，于末次免疫后14个月，使用柬埔寨来源的虫株克隆NF135.C10对其进行再次感染攻击（临床试验注册号：NCT01660854）。 结果：13名既往被NF54完全保护的志愿者中，有2名同样对NF135.C10实现完全保护性免疫；剩余11名志愿者则表现出延迟的疟原虫血症检出时间，其中位潜伏期为10.5天（范围9.0~15.5天），而5名疟疾未感染对照者的中位潜伏期为8.5天（P=0.0005）。通过实时定量聚合酶链反应（qPCR）对虫血症检出情况进行分析显示，11名部分获得保护的受试者中，有7名的肝脏疟原虫负荷预估降低了91%~>99%。另有3名既往未被NF54保护的志愿者，对NF135.C10同样未获得任何保护。 结论：本研究证实，CPS免疫可诱导持续一年以上的异源保护性免疫，这为全寄生虫疫苗的临床研发提供了进一步的推动依据。 试验注册：Clinicaltrials.gov NCT01660854