A Phase Ia Study to Assess the Safety and Immunogenicity of New Malaria
Vaccine Candidates ChAd63 CS administered alone and with MVA CS
Eoghan F. de Barra1, Susanne H. Sheehy2, Katie J. Ewer2, Kerrie Hennigan1, Ann Collins1, Ian D. Poulton2, Pooja Mange2, Katharine A. Collins2, Eleanor Berrie3, Sarah Moyle3, Alison
M. Lawrie2, Regitze Thoegersen5, Egeruan Babatunde Imoukhuede5, Odile Leroy5 , Alfredo Nicosia4, Samuel J. McConkey1, Adrian V. Hill2
1. Dept of International Health and Tropical Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland, 2. Centre for Clinical Vaccinology and Tropical Medicine, University of
Oxford, UK., Oxford, United Kingdom, 3. Clinical Biomanufacturing Facility, University of Oxford, UK., Oxford, United Kingdom, 4. Okairos, Pomezia, Rome, Italy, 5. European
Vaccine Initiative, UniversitätsKlinikum Heidelberg, Germany
ClinicalTrials.gov Identifier: NCT01450280
Presentation no. LB-273
Plasmodium falciparum malaria
Table 2: Overview of clinical trial groups: All vaccinations are
Immungenicity
intramuscular.
- Approximately 250 million cases and over 800,000 deaths worldwide in
2008, mostly in Africa.1
- Resistance
Both doses of ChAd63 CS were immunogenic, inducing high-level T cell
responses. Mean peak responses at day 14 post vaccination were 351 and
351.5 SFU/ million PBMC for doses of 5x109 vp and 5x1010 respectively. Peak
responses to MVA CS boosting were observed one week post vaccination,
(day 63); 1655 SFU/million PBMC (ChAd63 CS dose 5x109 vp); 1327
SFU/million PBMC (ChAd63 CS dose 5x1010 vp). The vaccine combination was
safe and well tolerated at both doses of ChAd63 CS.
Anopheles mosquitoes to certain insecticides
Malaria parasites to chemotherapeutic agents
-Need for a new, effective intervention for the prevention or treatment of
malaria.2
A vaccine against malaria
- Major goal of the Roll Back Malaria Partnership
- Felt to be a key future strategy for reducing mortality from malaria and moving
towards eradication.3
Introduction:
Inducing protective T-cell immunity against the malaria liver-stage parasite
is a key target of malaria vaccine development. Circumsporozoite Protein
(CS) expressed by sporozoites plays a key role in invasion into hepatocytes
and has shown promise as antigen in other vaccine candidates. Prime
boost vaccination utilising chimpanzee adenovirus 63 (ChAd63) and
modified vaccinia virus Ankara (MVA) replication-deficient viral vectored
vaccines expressing a range of antigens are in development and have
shown to be consistently immunogenic, inducing extremely potent T cell
responses.
Results
VACCINE Candidates – ChAd63 CS and MVA CS
Novel CS antigen, omits the extreme C-terminus of the protein that
encodes the GPI-anchor sequence and the N-terminal third of the protein
N-terminal to the central B cell repeat
Figure 4: ELISpot plate showing controls and Malaria peptide pools. One volunteer
from group 1A at 90 days post ChAd63 CS and one volunteer from group 1B 1 week
post MVA CS booster vaccine.
Prime : ChAd63 CS (Chimpanzee adenovirus 63
expressing circumsporozoite protein)
Boost: MVA CS (Modified vaccinia virus Ankara
expressing circumsporozoite protein)
Subject’s safety
Overview:
Serious adverse events (SAE)
To date there have been no SAE.
Suspected Unexpected Serious Adverse Reactions (SUSARs)
To date there have been no SUSARs.
Figure 5: ELISpot responses to CS peptides at day 14 and 63 post vaccination for both
doses of ChAd63 CS.
Adverse Events (AEs)
All AEs graded possibly, probably or definitely related to vaccination are
presented here. The highest grade of severity for each individual, for each AE
has been used. No significant difference in AE type or grade has been
observed between the two different doses of ChAd63 CS.
Figure 2a
Grade 1
Grade 2
Grade 3
Methods :
We conducted a Phase Ia, non-randomized clinical trial in 24 healthy,
malaria-naïve adults of the ChAd63 and MVA replication-deficient viral
vectored vaccines both encoding the circumsporozoite Protein of P.
falciparum. ChAd63-MVA CS was administered in a heterologous prime-boost
regime 8 weeks apart. Two different doses of ChAd63 CS were assessed
5x109 Viral Particles (vp)and 5x1010 vp following safety review. Serial
assessments of immune response were performed using Enzyme-Linked
Immunospot technique (ELISpot).
Table 1: Overview of clinical trial design and objectives
Figure 2b
Grade 1
Grade 2
Grade 3
Figure 6: ELISpot responses to CS peptides thoughout the study for groups 1A, 1B, 2A
and 2B.
Figure 2: VAC038: Adverse events (AEs) deemed possibly, probably or definitely
related to AdCh63 CS 5 x 109 vp and 5 x 1010. Figure 2a: Local AEs. ‘Other local AE’ =
paraesthesia at injection site lasting 2 days. Figure 2b: Systemic AEs. ‘Other systemic
AE’ = pruritus. ‘Lab’ = transient neutropenia
Figure 3a
Grade 1
Grade 2
Grade 3
Discussion
These data indicate adequate safety of this novel viral vectored vaccine
combination. The adverse events observed were of a nature seen with other
vaccines utilizing the same vectors and were all self limiting. The vast
majority were of minor severity. These data also establish a preferred dosing
of ChAd63 CS for induction of potent T cell immune responses.
The results of a phase II Controlled Human Malaria Infection study using this
vaccine combination are also being presented at this meeting (Abstract LB361). Investigations of the detailed humoral and cellular immunology are
ongoing.
Figure 3b
Grade 1
Grade 2
Grade 3
Acknowledgements:
We wish to thank the Irish Aid for financial support through the European
Vaccine Initiative and all the volunteers that participated in this study.
References
Figure 3 : VAC038: Adverse events (AEs) deemed possibly, probably or definitely related
to MVA CS 2 x 108 pfu. Figure 3a: Local AEs. Figure 3b: Systemic AEs. ‘Other systemic AE’ =
upper respiratory tract inflammation.
1. WHO. World Malaria Report. World Health Organization 2009.
2. White NJ. Antimalarial drug resistance. J Clin Invest 2004;113:1084-92.
3. Das P, Horton R. Malaria elimination: worthy, challenging, and just
possible. Lancet 2010;376:1515.
RCSI, 123 St. Stephen’s Green, Dublin 2, Ireland. edebarra@rcsi.ie