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Bulletin of the History of Medicine 2024Following the medical breakthroughs of Pasteur and Koch after 1880, the use of simians became pivotal to laboratory research to develop vaccines and cultivate microbes...
Following the medical breakthroughs of Pasteur and Koch after 1880, the use of simians became pivotal to laboratory research to develop vaccines and cultivate microbes through the technique of serial passage. These innovations fueled research on multiple diseases and unleashed a demand for simians, which died easily in captivity. European and American colonial expansion facilitated a burgeoning market for laboratory animals that intensified hunting for live animals. This demand created novel opportunities for disease transfers and viral recombinations as simians of different species were confined in precarious settings. As laboratories moved into the colonies for research into a variety of diseases, notably syphilis, sleeping sickness, and malaria, the simian market was intensified. While researchers expected that colonial laboratories offered more natural environments than their metropolitan affiliates, amassing apes, people, microbes, and insects at close quarters instead created unnatural conditions that may have facilitated the spread of undetectable diseases.
Topics: Animals; History, 20th Century; History, 19th Century; Colonialism; Laboratories; Animals, Laboratory; Humans; United States; Haplorhini; Animal Experimentation
PubMed: 38881469
DOI: 10.1353/bhm.2024.a929783 -
The Lancet. Infectious Diseases Jun 2024
PubMed: 38880114
DOI: 10.1016/S1473-3099(24)00356-6 -
The Lancet. Infectious Diseases Jun 2024A blood-stage Plasmodium falciparum malaria vaccine would provide a second line of defence to complement partially effective or waning immunity conferred by the approved...
Blood-stage malaria vaccine candidate RH5.1/Matrix-M in healthy Tanzanian adults and children; an open-label, non-randomised, first-in-human, single-centre, phase 1b trial.
BACKGROUND
A blood-stage Plasmodium falciparum malaria vaccine would provide a second line of defence to complement partially effective or waning immunity conferred by the approved pre-erythrocytic vaccines. RH5.1 is a soluble protein vaccine candidate for blood-stage P falciparum, formulated with Matrix-M adjuvant to assess safety and immunogenicity in a malaria-endemic adult and paediatric population for the first time.
METHODS
We did a non-randomised, phase 1b, single-centre, dose-escalation, age de-escalation, first-in-human trial of RH5.1/Matrix-M in Bagamoyo, Tanzania. We recruited healthy adults (aged 18-45 years) and children (aged 5-17 months) to receive the RH5.1/Matrix-M vaccine candidate in the following three-dose regimens: 10 μg RH5.1 at 0, 1, and 2 months (Adults 10M), and the higher dose of 50 μg RH5.1 at 0 and 1 month and 10 μg RH5.1 at 6 months (delayed-fractional third dose regimen; Adults DFx). Children received either 10 μg RH5.1 at 0, 1, and 2 months (Children 10M) or 10 μg RH5.1 at 0, 1, and 6 months (delayed third dose regimen; Children 10D), and were recruited in parallel, followed by children who received the dose-escalation regimen (Children DFx) and children with higher malaria pre-exposure who also received the dose-escalation regimen (High Children DFx). All RH5.1 doses were formulated with 50 μg Matrix-M adjuvant. Primary outcomes for vaccine safety were solicited and unsolicited adverse events after each vaccination, along with any serious adverse events during the study period. The secondary outcome measures for immunogenicity were the concentration and avidity of anti-RH5.1 serum IgG antibodies and their percentage growth inhibition activity (GIA) in vitro, as well as cellular immunogenicity to RH5.1. All participants receiving at least one dose of vaccine were included in the primary analyses. This trial is registered at ClinicalTrials.gov, NCT04318002, and is now complete.
FINDINGS
Between Jan 25, 2021, and April 15, 2021, we recruited 12 adults (six [50%] in the Adults 10M group and six [50%] in the Adults DFx group) and 48 children (12 each in the Children 10M, Children 10D, Children DFx, and High Children DFx groups). 57 (95%) of 60 participants completed the vaccination series and 55 (92%) completed 22 months of follow-up following the third vaccination. Vaccinations were well-tolerated across both age groups. There were five serious adverse events involving four child participants during the trial, none of which were deemed related to vaccination. RH5-specific T cell and serum IgG antibody responses were induced by vaccination and purified total IgG showed in vitro GIA against P falciparum. We found similar functional quality (ie, GIA per μg RH5-specific IgG) across all age groups and dosing regimens at 14 days after the final vaccination; the concentration of RH5.1-specific polyclonal IgG required to give 50% GIA was 14·3 μg/mL (95% CI 13·4-15·2). 11 children were vaccinated with the delayed third dose regimen and showed the highest median anti-RH5 serum IgG concentration 14 days following the third vaccination (723 μg/mL [IQR 511-1000]), resulting in all 11 who received the full series showing greater than 60% GIA following dilution of total IgG to 2·5 mg/mL (median 88% [IQR 81-94]).
INTERPRETATION
The RH5.1/Matrix-M vaccine candidate shows an acceptable safety and reactogenicity profile in both adults and 5-17-month-old children residing in a malaria-endemic area, with all children in the delayed third dose regimen reaching a level of GIA previously associated with protective outcome against blood-stage P falciparum challenge in non-human primates. These data support onward efficacy assessment of this vaccine candidate against clinical malaria in young African children.
FUNDING
The European and Developing Countries Clinical Trials Partnership; the UK Medical Research Council; the UK Department for International Development; the National Institute for Health and Care Research Oxford Biomedical Research Centre; the Division of Intramural Research, National Institute of Allergy and Infectious Diseases; the US Agency for International Development; and the Wellcome Trust.
PubMed: 38880111
DOI: 10.1016/S1473-3099(24)00312-8 -
Medicine Jun 2024Malaria remains an endemic public health concern in Africa, significantly contributing to morbidity and mortality rates. The inadequacies of traditional prevention... (Review)
Review
Malaria remains an endemic public health concern in Africa, significantly contributing to morbidity and mortality rates. The inadequacies of traditional prevention measures, like integrated vector management and antimalarial drugs, have spurred efforts to strengthen the development and deployment of malaria vaccines. In addition to existing interventions like insecticide-treated bed nets and artemisinin-based combination therapies, malaria vaccine introduction and implementation in Africa could drastically reduce the disease burden and hasten steps toward malaria elimination. The malaria vaccine rollout is imminent as optimistic results from final clinical trials are anticipated. Thus, determining potential hurdles to malaria vaccine delivery and uptake in malaria-endemic regions of sub-Saharan Africa will enhance decisions and policymakers' preparedness to facilitate efficient and equitable vaccine delivery. A multisectoral approach is recommended to increase funding and resources, active community engagement and participation, and the involvement of healthcare providers.
Topics: Humans; Malaria Vaccines; Malaria; Africa; Vaccination; Africa South of the Sahara
PubMed: 38875411
DOI: 10.1097/MD.0000000000038565 -
The Journal of Infectious Diseases Jun 2024A hallmark of cerebral malaria is sequestration of Plasmodium falciparum-infected erythrocytes (IEs) in the brain microcirculation. Antibodies contribute to malaria...
A hallmark of cerebral malaria is sequestration of Plasmodium falciparum-infected erythrocytes (IEs) in the brain microcirculation. Antibodies contribute to malaria immunity, but it remains unclear whether functional antibodies targeting parasite-expressed ligand can block cytoadhesion in the brain. Here, we screened the plasma of older children and young adults in Malawi to characterize the antibody response against the P. falciparum-IE surface and used a bioengineered 3D human brain microvessel model incorporating variable flow dynamics to measure adhesion blocking responses. We found a strong correlation between surface antibody reactivity by flow cytometry and reduced P. falciparum-IE binding in 3D microvessels. Moreover, there was a threshold of surface antibody reactivity necessary to achieve robust inhibitory activity. Our findings provide evidence of the acquisition of adhesion blocking antibodies against cerebral binding variants in people exposed to stable P. falciparum transmission and suggest the quality of the inhibitory response can be influenced by flow dynamics.
PubMed: 38875153
DOI: 10.1093/infdis/jiae315 -
Journal of Medical Virology Jun 2024Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence is used to estimate the proportion of individuals within a population previously...
Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence is used to estimate the proportion of individuals within a population previously infected, to track viral transmission, and to monitor naturally and vaccine-induced immune protection. However, in sub-Saharan African settings, antibodies induced by higher exposure to pathogens may increase unspecific seroreactivity to SARS-CoV-2 antigens, resulting in false positive responses. To investigate the level and type of unspecific seroreactivitiy to SARS-CoV-2 in Africa, we measured immunoglobulin G (IgG), IgA, and IgM to a broad panel of antigens from different pathogens by Luminex in 602 plasma samples from African and European subjects differing in coronavirus disease 2019, malaria, and other exposures. Seroreactivity to SARS-CoV-2 antigens was higher in prepandemic African than in European samples and positively correlated with antibodies against human coronaviruses, helminths, protozoa, and especially Plasmodium falciparum. African subjects presented higher levels of autoantibodies, a surrogate of polyreactivity, which correlated with P. falciparum and SARS-CoV-2 antibodies. Finally, we found an improved sensitivity in the IgG assay in African samples when using urea as a chaotropic agent. In conclusion, our data suggest that polyreactive antibodies induced mostly by malaria are important mediators of the unspecific anti-SARS-CoV-2 responses, and that the use of dissociating agents in immunoassays could be useful for more accurate estimates of SARS-CoV-2 seroprevalence in African settings.
Topics: Humans; COVID-19; Antibodies, Viral; Seroepidemiologic Studies; SARS-CoV-2; Immunoglobulin G; Adult; Male; Female; Middle Aged; Malaria; Immunoglobulin M; Young Adult; Aged; Adolescent; Europe; Immunoglobulin A; Endemic Diseases; Africa; Africa South of the Sahara
PubMed: 38874194
DOI: 10.1002/jmv.29713 -
Life Sciences Aug 2024Malaria is a major public health concern. The development of parasite-based vaccine RTS/AS01 has some therapeutic value but its lower efficacy is one of the major... (Review)
Review
Malaria is a major public health concern. The development of parasite-based vaccine RTS/AS01 has some therapeutic value but its lower efficacy is one of the major limitations. Mosquito-based transmission-blocking vaccines could have a higher potential for parasite inhibition within the mosquitoes. Several genes of mosquito midgut, salivary gland, hemolymph, etc. get activate in response to the Plasmodium-infected blood and helps in parasite invasion directly or indirectly inside the mosquito. The studies of such genes provided a new insight into developing the more efficient vaccines. In the field of malaria genetics research, RNAi has become an innovative strategy used to identify mosquito candidate genes for transmission-blocking vaccines. This review targeted the gene studies that have been conducted in the period 2000-2023 in different malaria vectors against different malarial parasites using the RNAi approach to reveal mosquito novel gene candidates for vaccine development.
Topics: Animals; RNA Interference; Malaria Vaccines; Anopheles; Malaria; Humans; Mosquito Vectors
PubMed: 38866221
DOI: 10.1016/j.lfs.2024.122822 -
PLoS Neglected Tropical Diseases Jun 2024Malaria transmission-blocking vaccines (TBVs) aim to inhibit malaria parasite development in mosquitoes and prevent further transmission to the human host. The...
BACKGROUND
Malaria transmission-blocking vaccines (TBVs) aim to inhibit malaria parasite development in mosquitoes and prevent further transmission to the human host. The putative-secreted ookinete protein 25 (PSOP25), highly conserved in Plasmodium spp., is a promising TBV target. Here, we investigated PvPSOP25 from P. vivax as a TBV candidate using transgenic murine parasite P. berghei and clinical P. vivax isolates.
METHODS AND FINDINGS
A transgenic P. berghei line expressing PvPSOP25 (TrPvPSOP25Pb) was generated. Full-length PvPSOP25 was expressed in the yeast Pichia pastoris and used to immunize mice to obtain anti-rPvPSOP25 sera. The transmission-blocking activity of the anti-rPvPSOP25 sera was evaluated through in vitro assays and mosquito-feeding experiments. The antisera generated by immunization with rPvPSOP25 specifically recognized the native PvPSOP25 antigen expressed in TrPvPSOP25Pb ookinetes. In vitro assays showed that the immune sera significantly inhibited exflagellation and ookinete formation of the TrPvPSOP25Pb parasite. Mosquitoes feeding on mice infected with the transgenic parasite and passively transferred with the anti-rPvPSOP25 sera showed a 70.7% reduction in oocyst density compared to the control group. In a direct membrane feeding assay conducted with five clinical P. vivax isolates, the mouse anti-rPvPSOP25 antibodies significantly reduced the oocyst density while showing a negligible influence on mosquito infection prevalence.
CONCLUSIONS
This study supported the feasibility of transgenic murine malaria parasites expressing P. vivax antigens as a useful tool for evaluating P. vivax TBV candidates. Meanwhile, the moderate transmission-reducing activity of the generated anti-rPvPSOP25 sera necessitates further research to optimize its efficacy.
Topics: Animals; Mice; Plasmodium vivax; Malaria Vaccines; Plasmodium berghei; Protozoan Proteins; Humans; Malaria, Vivax; Female; Antigens, Protozoan; Antibodies, Protozoan; Malaria; Mice, Inbred BALB C
PubMed: 38865344
DOI: 10.1371/journal.pntd.0012231 -
Frontiers in Immunology 2024Despite decades of effort, malaria remains a leading killer of children. The absence of a highly effective vaccine and the emergence of parasites resistant to both...
BACKGROUND
Despite decades of effort, malaria remains a leading killer of children. The absence of a highly effective vaccine and the emergence of parasites resistant to both diagnosis as well as treatment hamper effective public health interventions.
METHODS AND RESULTS
To discover new vaccine candidates, we used our whole proteome differential screening method and identified PfGBP130 as a parasite protein uniquely recognized by antibodies from children who had developed resistance to infection but not from those who remained susceptible. We formulated PfGBP130 as lipid encapsulated mRNA, DNA plasmid, and recombinant protein-based immunogens and evaluated the efficacy of murine polyclonal anti-PfGBP130 antisera to inhibit parasite growth in vitro. Immunization of mice with PfGBP130-A (aa 111-374), the region identified in our differential screen, formulated as a DNA plasmid or lipid encapsulated mRNA, but not as a recombinant protein, induced antibodies that inhibited RBC invasion . mRNA encoding the full ectodomain of PfGBP130 (aa 89-824) also generated parasite growth-inhibitory antibodies.
CONCLUSION
We are currently advancing PfGBP130-A formulated as a lipid-encapsulated mRNA for efficacy evaluation in non-human primates.
Topics: Animals; Plasmodium falciparum; Antibodies, Protozoan; Mice; Erythrocytes; Malaria, Falciparum; Humans; Malaria Vaccines; Protozoan Proteins; Antigens, Protozoan; Immunization; Female
PubMed: 38863702
DOI: 10.3389/fimmu.2024.1350560 -
Nature Reviews. Immunology Jun 2024Malaria, caused by infection with Plasmodium parasites, drives multiple regulatory responses across the immune landscape. These regulatory responses help to protect... (Review)
Review
Malaria, caused by infection with Plasmodium parasites, drives multiple regulatory responses across the immune landscape. These regulatory responses help to protect against inflammatory disease but may in some situations hamper the acquisition of adaptive immune responses that clear parasites. In addition, the regulatory responses that occur during Plasmodium infection may negatively affect malaria vaccine efficacy in the most at-risk populations. Here, we discuss the specific cellular mechanisms of immunoregulatory networks that develop during malaria, with a focus on knowledge gained from human studies and studies that involve the main malaria parasite to affect humans, Plasmodium falciparum. Leveraging this knowledge may lead to the development of new therapeutic approaches to increase protective immunity to malaria during infection or after vaccination.
PubMed: 38862638
DOI: 10.1038/s41577-024-01041-5