Preimmunization correlates of protection shared across malaria vaccine trials in adults

Identifying preimmunization biological characteristics that promote an effective vaccine response offers opportunities for illuminating the critical immunological mechanisms that confer vaccine-induced protection, for developing adjuvant strategies, and for tailoring vaccination regimens to individuals or groups. In the context of malaria vaccine research, studying preimmunization correlates of protection can help address the need for a widely effective malaria vaccine, which remains elusive. In this study, common preimmunization correlates of protection were identified using transcriptomic data from four independent, heterogeneous malaria vaccine trials in adults. Systems-based analyses showed that a moderately elevated inflammatory state prior to immunization was associated with protection against malaria challenge. Functional profiling of protection-associated genes revealed the importance of several inflammatory pathways, including TLR signaling. These findings, which echo previous studies that associated enhanced preimmunization inflammation with protection, illuminate common baseline characteristics that set the stage for an effective vaccine response across diverse malaria vaccine strategies in adults.

Willingness to pay for a hypothetical malaria vaccine in Brazil: a cross-sectional study and the implications

Aim: Malaria is an infection caused by protozoa of genus Plasmodium, considered the one associated with increasingly large outbreaks. Methods: A cross-sectional study was conducted with residents in the northern region of Brazil on the willingness to pay (WTP) for a hypothetical vaccine against malaria (effective protection of 80%). Results: Of 616 people interviewed, most interviewees were female (61%) and were employed (97%). The median individual maximum WTP for a hypothetical malaria vaccine was US$11.90 (BRL 50). Conclusion: The northern region of Brazil is one of the largest markets for a malaria vaccine due to its epidemiological relevance. Consequently, economic studies will be important to assist in the assessment of the potential price and value of new vaccines.

Genetic Diversity and Selection of Plasmodium vivax Apical Membrane Antigen-1 in China–Myanmar Border of Yunnan Province, China, 2009–2016

Plasmodium vivax apical membrane antigen-1 (PvAMA-1) is an important vaccine candidate for vivax malaria. However, antigenic variation within PvAMA-1 is a major obstacle to the design of a global protective malaria vaccine. In this study, we analyzed the genetic polymorphism and selection of the PvAMA-1 gene from 152 P. vivax isolates from imported cases to China, collected in the China–Myanmar border (CMB) area in Yunnan Province (YP) during 2009–2011 (n = 71) and 2014–2016 (n = 81), in comparison with PvAMA-1 gene information from Myanmar (n = 73), collected from public data. The overall nucleotide diversity of the PvAMA-1 gene from the 152 YP isolates was 0.007 with 76 haplotypes identified (Hd = 0.958). Results from the population structure suggested three groups among the YP and Myanmar isolates with optimized clusters value of K = 7. In addition, YP (2014–2016) isolates generally lacked some K components that were commonly found in YP (2009–2011) and Myanmar. Meanwhile, PvAMA-1 domain I is found to be the dominant target of positive diversifying selection and most mutation loci were found in this domain. The mutation frequencies of D107N/A, R112K/T, K120R, E145A, E277K, and R438H in PvAMA-1 were more than 70% in the YP isolates. In conclusion, high genetic diversity and positive selection were found in the PvAMA-1 gene from YP isolates, which are significant findings for the design and development of PvAMA-1-based malaria vaccine.

A PROTEÍNA PfGARP COMO POSSÍVEL CANDIDATA À VACINA ANTIMALÁRICA

Introdução: A malária é uma parasitose que, apesar de antiga, continua sendo um grande risco para saúde pública com cerca de 445 mil mortes por ano ao redor do mundo(2). Apesar de possuir cinco agentes etiológicos, o Plasmodium falciparum é o principal, sendo responsável pelo maior número de mortes por malária(1,2). Uma vez que há diversos empecilhos quando se trata da erradicação da malária como resistência a inseticidas e a drogas antimaláricas, foi observada a necessidade de uma vacina contra o agravamento dessa parasitose(1). O fato de que a fase sanguínea do Plasmodium é atualmente apontada como um dos possíveis alvos para a ação de uma vacina, fez os pesquisadores enxergarem a proteína rica em ácido glutâmico do P. falciparum (PfGARP) que é encontrada na superfície das células vermelhas infectadas pelo parasita(2,3). Assim, fez-se necessária uma pesquisa com os anticorpos contra essa proteína para melhor elucidação. Objetivos: O objetivo deste resumo é observar os efeitos dos anticorpos anti-PfGARP contra trofozoítos do Plasmodium falciparum e como esses anticorpos oferecem proteção contra o agravamento da malária. Métodos: Foi realizada a procura nas plataformas científicas PubMed e Google Acadêmico e os artigos utilizados foram encontrados por meio do descritor “malaria vaccine”. Resultados: Os anticorpos anti-PfGARP presentes nos indivíduos estudados foram apontados como responsáveis pela diminuição da integridade morfológica dos parasitas, onde os mesmos apresentaram-se picnóticos, característicos de morte(3). Além disso, esses anticorpos causaram uma diminuição da integridade do vacúolo digestivo, apresentando-se com um tamanho menor ou até mesmo ausente(3). Outrossim, os parasitas sofreram alterações no potencial de membrana mitocondrial, tendo a mitocôndria perdido função após 24h(3). Por fim, os anticorpos anti-PfGARP ativaram a morte celular programada desses parasitas por meio da ativação de caspases(3). Conclusões: Com base no que foi exposto, é possível concluir que a PfGARP é uma excelente candidata para o desenvolvimento de uma vacina contra o Plasmodium falciparum por meio da morte dos parasitas. Sendo assim, é necessário que sejam realizados mais estudos com a PfGARP com o objetivo de obter mais informações acerca dos benefícios de uma vacina com essa proteína e, ainda, conhecer possíveis malefícios para que possa ser inclusa no mercado de forma eficaz e segura, diminuindo a ocorrência de malária grave e assim evitando o sofrimento de milhares de pessoas infectadas com esta parasitose ao redor do mundo.

Genome, proteome, and immunome data explain why 6 month controlled human malaria infection with sporozoites of the Pf7G8 clone of Plasmodium falciparum is a rigorous predictor of the efficacy of the PfNF54-based PfSPZ Vaccine in Africa

Controlled human malaria infection (CHMI) has supported Plasmodium falciparum (Pf) malaria vaccine development by providing preliminary estimates of vaccine efficacy (VE). Because CHMIs generally use Pf strains similar to vaccine strains, VE against antigenically heterogeneous Pf in the field has been required to establish VE. We increased the stringency of CHMI by selecting a Brazilian isolate, Pf7G8, which is genetically distant from the West African parasite (PfNF54) in our PfSPZ vaccines. Using two regimens to identically immunize US and Malian adults, VE over 24 weeks in the field was as good as or better than against CHMI at 24 weeks in the US. To explain this finding, we quantified differences in the genome, proteome and predicted CD8 T cell epitopes of PfNF54 relative to 709 Pf isolates from Africa and Pf7G8. Pf7G8 is more distant from PfNF54 than any African isolates tested. We propose VE against Pf7G8 CHMI for providing pivotal data for malaria vaccine licensure for travelers to Africa, and potentially for endemic populations, because the genetic distance of Pf7G8 from the Pf vaccine strain makes it a stringent surrogate for Pf parasites in Africa.

Antibody Targets and Properties for Complement-Fixation Against the Circumsporozoite Protein in Malaria Immunity

The Plasmodium falciparum circumsporozoite protein (CSP) forms the basis of leading subunit malaria vaccine candidates. However, the mechanisms and specific targets of immunity are poorly defined. Recent findings suggest that antibody-mediated complement-fixation and activation play an important role in immunity. Here, we investigated the regions of CSP targeted by functional complement-fixing antibodies and the antibody properties associated with this activity. We quantified IgG, IgM, and functional complement-fixing antibody responses to different regions of CSP among Kenyan adults naturally exposed to malaria (n=102) and using a series of rabbit vaccination studies. Individuals who acquired functional complement-fixing antibodies had higher IgG, IgM and IgG1 and IgG3 to CSP. Acquired complement-fixing antibodies targeted the N-terminal, central-repeat, and C-terminal regions of CSP, and positive responders had greater antibody breadth compared to those who were negative for complement-fixing antibodies (p<0.05). Using rabbit vaccinations as a model, we confirmed that IgG specific to the central-repeat and non-repeat regions of CSP could effectively fix complement. However, vaccination with near full length CSP in rabbits poorly induced antibodies to the N-terminal region compared to naturally-acquired immunity in humans. Poor induction of N-terminal antibodies was also observed in a vaccination study performed in mice. IgG and IgM to all three regions of CSP play a role in mediating complement-fixation, which has important implications for malaria vaccine development.