Heterologous Protection against Malaria after Immunization with Plasmodium falciparum Sporozoites

Abstract

Background: Sterile 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.

Methods: In 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).

Results: Two 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.

Conclusion: This 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 registration: Clinicaltrials.gov NCT01660854.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. Study flow diagram.

The previous NF54 CPS-immunization study is shown in grey. P = NF54 protected, NP = NF54 unprotected. ⨂ = Volunteer presumptively treated on day 10.5 after NF54 challenge and considered NF54 protected

Fig 2. Protection and prepatent period after heterologous NF135.C10 challenge.

Left panels: Kaplan-Meier curves showing percentage of thick smear negative volunteers after NF135.C10 challenge according to previous NF54 protection status (A) and NF54 CPS-immunization dose (C). Right panels: The corresponding distribution of prepatent period of thick smear positive volunteers is shown in dot plots according to NF54 protection status (B) and NF54 CPS-immunization dose (D). Lines represent medians. ⨂ = Volunteer presumptively treated after NF54 challenge and considered NF54 protected.

Fig 3. Parasitemia before and after treatment.

Parasitemia measured by qPCR up until initiation of treatment (A and C) and from treatment onwards (B and D) in previously NF54 protected volunteers (A and B) and controls (C and D). Each line represents an individual subject with the same colour before and after treatment. Values shown as 25 Pf/ml were negative (i.e. half the detection limit of the qPCR: 50 parasites/ml).

Fig 4. Adverse events before and after initiation of treatment.

Average number of possibly and probably related (both solicited and unsolicited) AE per previously NF54 protected or control volunteer in relation to the time of positive thick smear (day of treatment). Time points are plotted towards day of treatment, depicted as ‘T’, from 3 days before until 7 days after start of treatment.