Developing tuberculosis vaccines for people with HIV: consensus statements from an international expert panel.

New tuberculosis vaccine candidates that are in the development pipeline need to be studied in people with HIV, who are at high risk of acquiring Mycobacterium tuberculosis infection and tuberculosis disease and tend to develop less robust vaccine-induced immune responses. To address the gaps in developing tuberculosis vaccines for people with HIV, a series of symposia was held that posed six framing questions to a panel of international experts: What is the use case or rationale for developing tuberculosis vaccines? What is the landscape of tuberculosis vaccines? Which vaccine candidates should be prioritised? What are the tuberculosis vaccine trial design considerations? What is the role of immunological correlates of protection? What are the gaps in preclinical models for studying tuberculosis vaccines? The international expert panel formulated consensus statements to each of the framing questions, with the intention of informing tuberculosis vaccine development and the prioritisation of clinical trials for inclusion of people with HIV.

Glycophorin C (Gerbich antigen blood group) and band 3 polymorphisms in two malaria holoendemic regions of Papua New Guinea.

The geographic overlap between the prevalence of erythrocyte polymorphisms and malaria endemicity is thought to be an example of natural selection on human populations. In Papua New Guinea (PNG), the Gerbich-negative phenotype is caused by an exon 3 deletion in the glycophorin C gene (GYPCDeltaex3) while heterozygosity for a 27-base pair deletion in the SLC4A1 gene (anion exchanger 1 or erythrocyte membrane protein, band 3), SLC4A1Delta27, results in Southeast Asian ovalocytosis. Two geographically and ethnically distinct malaria endemic regions of PNG (the Wosera [East Sepik Province] and Liksul [Madang Province]) were studied to illustrate the distribution of two prominent deletion polymorphisms (GYPCDeltaex3 and SLC4A1Delta27) and to determine if the genetic load associated with SLC4A1Delta27 would constrain independent assortment of GYPCDeltaex3 heterozygous and homozygous genotypes. The frequency of the GYPCDeltaex3 allele was higher in the Wosera (0.463) than Liksul (0.176) (chi(2); P < 0.0001). Conversely, the frequency of the SLC4A1Delta27 allele was higher in Liksul (0.0740) than the Wosera (0.0005) (chi(2); P < 0.0001). No individuals were homozygous for SLC4A1Delta27. In 355 Liksul residents, independent assortment of these two deletion polymorphisms resulted in 14 SLC4A1Delta27 carriers heterozygous for GYPCDeltaex3 and one SLC4A1Delta27 carrier homozygous for GYPCDeltaex3 (Fisher's exact test; P = 0.8040). While homozygosity for SLC4A1Delta27 appears to be nonviable, the GYPCDeltaex3 allele is not lethal when combined with SLC4A1Delta27. Neither mutation was associated with altered susceptibility to asymptomatic Plasmodium falciparum or P. vivax infection. While these erythrocyte polymorphisms apparently have no effect on blood-stage malaria infection, their contribution to susceptibility to clinical malaria morbidity requires further study.

Erythrocyte polymorphisms and malaria parasite invasion in Papua New Guinea.

Plasmodium falciparum merozoites engage the erythrocyte surface through several receptor (host)-ligand (parasite) interactions during a brief exchange that results in parasite invasion of the red blood cell. Tens of thousands of these events occur during the initial cycle of blood-stage infections but advance towards billions as the parasite becomes visible to microscopists attempting to diagnose the underlying cause of illness in febrile patients. Advancing blood-stage infection leads to massive proportions of erythrocytes that rupture during repetitive cycles of asexual reproduction. As the infection leads to illness, non-immune or semi-immune individuals can suffer from life-threatening consequences of severe malarial anemia that play a leading role in pathogenesis. Through natural selection, some erythrocyte membrane polymorphisms are likely to have reduced the invasion success of the P. falciparum merozoite and increased the fitness of the human host population.

Plasmodium falciparum erythrocyte invasion through glycophorin C and selection for Gerbich negativity in human populations.

Geographic overlap between malaria and the occurrence of mutant hemoglobin and erythrocyte surface proteins has indicated that polymorphisms in human genes have been selected by severe malaria. Deletion of exon 3 in the glycophorin C gene (called GYPCDeltaex3 here) has been found in Melanesians; this alteration changes the serologic phenotype of the Gerbich (Ge) blood group system, resulting in Ge negativity. The GYPCDeltaex3 allele reaches a high frequency (46.5%) in coastal areas of Papua New Guinea where malaria is hyperendemic. The Plasmodium falciparum erythrocyte-binding antigen 140 (EBA140, also known as BAEBL) binds with high affinity to the surface of human erythrocytes. Here we show that the receptor for EBA140 is glycophorin C (GYPC) and that this interaction mediates a principal P. falciparum invasion pathway into human erythrocytes. EBA140 does not bind to GYPC in Ge-negative erythrocytes, nor can P. falciparum invade such cells using this invasion pathway. This provides compelling evidence that Ge negativity has arisen in Melanesian populations through natural selection by severe malaria.