https://orcid.org/0000-0002-2946-5456
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ABSTRACT
Introduction
Malaria, a devastating febrile illness caused by protozoan parasites, sickened 247,000,000 people in 2021 and killed 619,000, mostly children and pregnant women in sub-Saharan Africa. A highly effective vaccine is urgently needed, especially for Plasmodium falciparum (Pf), the deadliest human malaria parasite.
Areas covered
Sporozoites (SPZ), the parasite stage transmitted by Anopheles mosquitoes to humans, are the only vaccine immunogen achieving >90% efficacy against Pf infection. This review describes >30 clinical trials of PfSPZ vaccines in the U.S.A., Europe, Africa, and Asia, based on first-hand knowledge of the trials and PubMed searches of ‘sporozoites,’ ‘malaria,’ and ‘vaccines.’
Expert opinion
First generation (radiation-attenuated) PfSPZ vaccines are safe, well tolerated, 80–100% efficacious against homologous controlled human malaria infection (CHMI) and provide 18–19 months protection without boosting in Africa. Second generation chemo-attenuated PfSPZ are more potent, 100% efficacious against stringent heterologous (variant strain) CHMI, but require a co-administered drug, raising safety concerns. Third generation, late liver stage-arresting, replication competent (LARC), genetically-attenuated PfSPZ are expected to be both safe and highly efficacious. Overall, PfSPZ vaccines meet safety, tolerability, and efficacy requirements for protecting pregnant women and travelers exposed to Pf in Africa, with licensure for these populations possible within 5 years. Protecting children and mass vaccination programs to block transmission and eliminate malaria are long-term objectives.
Article highlights
Since the 1970s, radiation-attenuated Plasmodium falciparum (Pf) sporozoites (SPZ) inoculated into humans by mosquito bite have been known to induce high-level immunity to Pf malaria infection, but this was never considered a practical approach to vaccination.
Sanaria Inc. has developed regulatory-compliant methods for the production of aseptic, purified, vialed, cryopreserved PfSPZ using mosquitoes as the ‘bioreactor,’ which can be injected with a needle and syringe to protect travelers and residents of malaria-endemic areas.
First generation, radiation-attenuated PfSPZ, called Sanaria® PfSPZ Vaccine, are safe, well tolerated, and protect 80–100% of recipients against homologous (same strain) controlled human malaria infection (CHMI) at 3 weeks and up to 60% of recipients against naturally transmitted Pf malaria for at least 18–19 months without boosting.
Second generation, chemo-attenuated PfSPZ, called Sanaria® PfSPZ-CVac, replicate in the liver, amplifying the immunogen and increasing potency, and achieve 100% protection against heterologous (variant strain) CHMI at 12 weeks at ~20% the dose of PfSPZ Vaccine, but pose a safety risk due to the requirement for co-administered drug.
Third generation, genetically attenuated PfSPZ, such as Sanaria®PfSPZ-LARC2 Vaccine, replicate in the liver like chemo-attenuated PfSPZ but spontaneously arrest development without the need for a partner drug, and will be tested in humans in 2023-2024. PfSPZ-LARC2 Vaccine is expected to have the safety of PfSPZ Vaccine and the efficacy of PfSPZ-CVac.
Sanaria is developing in vitro production of PfSPZ to replace current production in aseptic mosquitoes. Once standardized for GMP manufacture, in vitro production will provide ample PfSPZ to meet the world’s needs as well as a 90% reduction in the cost of goods.
Biological challenges faced by developers include the reduced immunogenicity of PfSPZ vaccines in malaria-exposed persons living in endemic areas and the antigenic diversity of the Pf malaria parasite.
PfSPZ vaccines are optimally administered by direct venous inoculation in 0.3 to 0.5 mL, a quick (seconds) and nearly painless procedure representing a new skill to be acquired by clinical teams.
PfSPZ vaccines require a liquid nitrogen vapor phase (LNVP) cold chain for cryostabilization, which allows delivery to remote locations without the need for electricity, ideal for mass vaccination programs designed to halt transmission and eliminate malaria from defined geographic areas.
We estimate that, with adequate funding, a PfSPZ vaccine will be licensed for use within the next 5 years.
Declaration of interests
Thomas L. Richie, L.W. Preston Church, Tooba Murshedkar, Peter F. Billingsley, Eric R. James, Mei-Chun Chen, Yonas Abebe, Natasha KC, Sumana Chakravarty, David Dolberg, B. Kim Lee Sim, and Stephen L. Hoffman are salaried, full-time employees of Sanaria Inc. B. Kim Lee Sim and Stephen L. Hoffman own stock in Sanaria. Benjamin Mordmüller has a consultancy agreement on vaccine development with Nobelpharma Co., Ltd., Japan. Robert W. Sauerwein has stock ownership in TropIQ Health Sciences, Nijmegen, The Netherlands. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Disclaimer
The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention, or the National Institutes of Health.
Author contributions
All authors have contributed to the conception and design of the review article and interpreting the relevant literature and have been involved in writing the review article or revised it for intellectual content.
Dedication
This review is dedicated to Shahid Kahn, our dear friend, inspirational colleague and brilliant pioneer in the field of genetically altered parasites, and to Ogobara Doumbo, extraordinary leader, beloved mentor, clinical trial champion, shepherd of international good will, and lion in the fight against malaria. Both are sorely missed.
Acknowledgments
We warmly thank the many institutions, investigators, and their teams who were or are involved in the conduct of completed, ongoing, and planned trials of PfSPZ products, for their collaboration and, in many cases, financial support (listed by institution in alphabetical order):
Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD, United States: Zonghui Hu, Martha Nason, Jing Wang, Erin E. Gabriel; Centers for Disease Control, Atlanta, GA, United States: Julie Gutman, Ryan Wiegand, Aaron Samuels, Patrick Kachur; Centre National de Recherche et de Formation sur le Paludisme (CNRFP) and Groupe de Recherche Action en Santé (GRAS), Ouagadougou, Burkina Faso: Alphonse Ouedraogo, Alfred Tiono, Edith Bougouma, Issa Diarra; CERMEL (Centre de Recherches Médicales de Lambaréné), Lambaréné, Gabon: Anita Lumeka Kabwende, Jean-Claude Dejon Agobe, Jeannot Zinzou, Bertrand Lell, Pamela Minsoko, Armel Mbouna, Ayodele Alabi; Equatorial Guinea Ministry of Health and Social Welfare, Malabo, Equatorial Guinea: Mitoha Ondo’o Ayekaba, Diosdado Nsue Milang, Vicente Urbano Nsue Ndong Nchama, Juan Carlos Momo Besaha, Antonio Enrique Ngua Sama Roca, Genaro Nsue Nguema, Beltran Ekua Pasialo, Martín Eka Ondó Mangue, Gertrudis Owono Bidjimi, Marta Alene Owono Eyang, Escolastica Raquel Mansogo Maye, José Raso, Fortunata Lobede, Dolores Mbang, Esther Eburi; Emmes Corporation: David Styers, Claire Stablein, Gail Potter; Ifakara Health Institute, Bagamoyo, United Republic of Tanzania: Ali Hamad, Ali Mtoro, Kamaka Ramadhani, Maximillian Mpina, Elizabeth Nyakarungu, Mwajuma Chemba, Thabit Athuman, Ummi Abdul; Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore: Ankit Dwivedi, Kara Moser, Myron Levine; Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany: Mihály Sulyok, Rolf Fendel, Zita Sulyok, Steffen Borrmann, Albert Lalremruata, Annette Knoblich, Markus Gmeiner, Jaana Heinze, Diane Egger-Adam; Kaiser Permanente Washington Health Research Institute (formerly Group Health), Seattle, WA, United States: Lisa Jackson; Kenya Medical Research Institute (KEMRI), Wellcome Trust, and Centre for Research in Therapeutic Sciences (CREATES), Nairobi, Kenya: Simon Kariuki, Philip Bejon, Kephas Otieno, Tony Sang, Reuben Yego Cherop; Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, United States: Agnes Mwakingwe-Omari, Irfan Zaidi, J. Patrick Gorres, Aye Diallo, Blair J. Wylie, Alemush Imeru, Emily Higbee, Kelly Rausch, Rathy Mohan, Viyada Doan, Kelly Ding, Regina White, Sharon Wong-Madden, Maria Conner, Jacquelyn Lane, Freda Omaswa; Leiden University Medical Center, Leiden, the Netherlands: Shahid Kahn; Liverpool School of Tropical Medicine: Feiko Ter Kuile; Malaria Research Group, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, United States: Andrea Berry, Colleen Boyce, Alison Kwon; Malaria Research and Training Center, University of Bamako, Bamako, Mali: Ogobara Doumbo, Mahamadou Thera, Drissa Coulibaly, Amagana Dolo, Mahamadoun H. Assadou, Abdoulaye Katile, Bourama Kamate, Djibrilla Issiaka, Kourane Sissoko, Amatigue Zeguime, Merepen A. Guindo, M’Bouye Doucoure, Kalifa Diarra, Oumar Attaher, Amadou Niangaly, Balla Diarra, Karamoko Niare, Ismaili Thera; Marathon Oil: Carl Maas, Bonifacio Manguire Nlavo; Medical Care Development International, Malabo, Equatorial Guinea: Guillermo Garcia, Chris Schwabe, Carlos Cortes Falla, Wonder Phiri, Jeremias Nzamio; Jordan Smith; Naval Medical Research Center, Silver Spring, MD, United States: Alexandra Singer, Martha Sedegah, Eileen Villasante; Oxford University Clinical Research Unit Indonesia (OUCRU Indonesia), University of Indonesia Faculty of Medicine, Eijkman Institute of Molecular Biology, Indonesian Army, Jakarta, Indonesia: Erni Nelwan, J. Kevin Baird, Krisin Chand, Amin Soebandrio, Rintis Noviyanti, Nur Abdul Ghoni, Yogi Ertanto, Decy Subekti, Rizka Fahmia, Mutia Rahardjani, Fitri Wulandari; Michael Christian, Samuel Manalu, Khoriah Indrihutami, Margareta Oktaviani, Rara Aulia, Marillyn Tamburian, Agus Rachmat, Yulia Widya; Radboud University Medical Center, Nijmegen, the Netherlands: Guido Bastiaens, Else Bijker, Cornelus Hermsen, Ben van Schaijk; Sanaria Inc./Protein Potential, Rockville, MD, United States: The manufacturing, quality, regulatory, clinical, logistics, immunology, pharmaceutical operations, administrative, legal, and project management teams including, Abraham Eappen, Tao Li, Minglin Li, Jeremy Guth, Anita Manoj, Anusha Gunasekera, Asha Patil, LiXin Gao, Rui Xu, Faith Beams, Maria Orozco, Bing Jiang, Shachi Shah, Thomas Stabler, Raul Chuquiyauri, Steve Manock, Pouria Riyahi, Elizabeth Saverino, Ravi Punjabi, Diana Perez, Sue Rupprecht, Alexander Hoffman, Chris Carmona, Laurence Lemiale; Sanaria contractors: Almudena Llegarda, Ninky Acevedo; Seattle Children’s Research Institute, Seattle, WA, USA: Deba Goswami, Nelly Camargo, Will Betz, Janna Gibson, Kenza Oualim, Silvia Arredondo; Seattle Malaria Clinical Trials, Fred Hutchinson Cancer Center: Elizabeth Duke, Dianna Hergott, Gift Nwanne; Swiss Tropical and Public Health Institute, Basel, Switzerland: Tobias Schindler, Tobias Rutishauser, Anna Deal; University of Massachusetts: Anne Moormann; University of Washington, Seattle, WA, United States: Annette M. Seilie, Ming Chang; Vaccine Research Center, National Institute of Allergy and Infectious Disease, NIH, Bethesda, MD, United States: Robert Seder, Julie Ledgerwood.
We gratefully acknowledge the past and current support of the following funding institutions: the Division of Microbiology and Infectious Diseases, NIAID, NIH, which has supported discovery research, preclinical development including manufacturing and quality control release, clinical trials and nonclinical activities; the Laboratory of Malaria Immunology and Vaccinology, NIAID, NIH; the Vaccine Research Center, NIAID, NIH; the Government of Equatorial Guinea and Marathon Oil Corporation (in partnership with EG LNG, AMPCO, and Noble Energy); the US Navy Advanced Medical Development Program; the Military Infectious Disease Research Program; the Congressionally Directed Medical Research Program; the US Army Medical Materiel Development Activity; PATH Malaria Vaccine Initiative (Bill & Melinda Gates Foundation [BMGF]); Institute for OneWorld Health (BMGF); the BMGF; TI Pharma; the European Union Malaria Fund; the German Centre for Infection Research (DZIF); the Swiss State Secretariat for Education, Research and Innovation; the Tanzanian Commission on Science and Technology (COSTECH); the European & Developing Countries Clinical Trials Partnership (EDCTP); the Wellcome Trust; the Broad Institute; and the Medicines for Malaria Venture.
We express our appreciation to the 2046 research volunteers who have participated to date in trials of Sanaria PfSPZ vaccines.
Notes
1. Heterologous = challenge strain genetically and antigenically distinct from the vaccine strain, making heterologous CHMI a more stringent assessment of VE than homologous CHMI.
2. Homologous = challenge strain the same as the vaccine strain.
3. The terms sterile immunity and sterile protection as used in this review mean that no parasitemia is detected during CHMI follow-up, indicating complete blockade of parasite development prior to the blood stage. The modifier ‘sterile’ is used because partially effective vaccines have been credited with inducing immunity when liver burdens have been reduced or the prepatent period to blood stage infection has been lengthened, even though trial participants undergoing CHMI have developed parasitemia.
4. Adenovirus, Mycobacterium tuberculosis, Vibrio cholera, dengue virus, Ebola vírus, influenza virus, measles virus, mumps virus, rubella virus, rotavirus, variola and monkeypox viruses, Salmonella Typhi, varicella-zoster virus, yellow fever virus and poliovirus (previously licensed; now replaced with inactivated polio virus vaccine).
5. Bacillus anthracis, hepatitis A virus, Japanese encephalitis virus, Yersinia pestis, tick-borne encephalitis virus, rabies virus.
6. 5/5 was the result of the first of three CHMI’s. After all three CHMI’s were conducted in the two phases of this trial, at total of 15/17 participants receiving three doses remained parasite free in the blood after homologous CHMI.
7. NF54, the vaccine strain, was isolated in 1979 from a Dutch farmer living near the Amsterdam Schiphol airport, presumably transmitted by an infected mosquito riding on an airplane from a malaria endemic area, since the farmer had never left the Netherlands and had not received a blood transfusion or any other procedure that might have transmitted malaria; genomic analysis strongly suggests that the strain is West African in origin.
8. Clearance was performed after the third (last) immunization so that new infections could be identified. It was not understood at that time that it should have been performed before the third immunization, fulfilling two purposes at once: allowing new infections to be identified during surveillance and reducing immune suppression during the third immunization.
9. The ability to produce abundant stage V gametocytes in culture and high sporozoite yields in the salivary glands of mosquitoes fed on those cultures are key attributes required for the successful manufacture of PfSPZ Challenge. Pf7G8 has been selected at this point as a primary strain for heterologous CHMI because it is a reasonably good producer of gametocytes/oocysts/sporozoites (although not as good as PfNF54), but Sanaria is now developing divergent strains of PfSPZ Challenge from East Africa (PfNF54 is from West Africa) and from Southeast Asia to expand the stringency and geographic representation of heterologous CHMI.