T follicular helper 17 (Tfh17) cells are superior for immunological memory maintenance.

A defining feature of successful vaccination is the ability to induce long-lived antigen-specific memory cells. T follicular helper (Tfh) cells specialize in providing help to B cells in mounting protective humoral immunity in infection and after vaccination. Memory Tfh cells that retain the CXCR5 expression can confer protection through enhancing humoral response upon antigen re-exposure but how they are maintained is poorly understood. CXCR5+ memory Tfh cells in human blood are divided into Tfh1, Tfh2, and Tfh17 cells by the expression of chemokine receptors CXCR3 and CCR6 associated with Th1 and Th17, respectively. Here, we developed a new method to induce Tfh1, Tfh2, and Tfh17-like (iTfh1, iTfh2, and iTfh17) mouse cells in vitro. Although all three iTfh subsets efficiently support antibody responses in recipient mice with immediate immunization, iTfh17 cells are superior to iTfh1 and iTfh2 cells in supporting antibody response to a later immunization after extended resting in vivo to mimic memory maintenance. Notably, the counterpart human Tfh17 cells are selectively enriched in CCR7+ central memory Tfh cells with survival and proliferative advantages. Furthermore, the analysis of multiple human cohorts that received different vaccines for HBV, influenza virus, tetanus toxin or measles revealed that vaccine-specific Tfh17 cells outcompete Tfh1 or Tfh2 cells for the persistence in memory phase. Therefore, the complementary mouse and human results showing the advantage of Tfh17 cells in maintenance and memory function supports the notion that Tfh17-induced immunization might be preferable in vaccine development to confer long-term protection.

Innate immunity to malaria: The good, the bad and the unknown.

Malaria is the cause of 600.000 deaths annually. However, these deaths represent only a tiny fraction of total malaria cases. Repeated natural infections with the causative agent, Plasmodium sp. parasites, induce protection from severe disease but not sterile immunity. Thus, immunity to Plasmodium is incomplete. Conversely, immunization with attenuated sporozoite stage parasites can induce sterile immunity albeit after multiple vaccinations. These different outcomes are likely to be influenced strongly by the innate immune response to different stages of the parasite lifecycle. Even small numbers of sporozoites can induce a robust proinflammatory type I interferon response, which is believed to be driven by the sensing of parasite RNA. Moreover, induction of innate like gamma-delta cells contributes to the development of adaptive immune responses. Conversely, while blood stage parasites can induce a strong proinflammatory response, regulatory mechanisms are also triggered. In agreement with this, intact parasites are relatively weakly sensed by innate immune cells, but isolated parasite molecules, notably DNA and RNA can induce strong responses. Thus, the innate response to Plasmodium parasite likely represents a trade-off between strong pro-inflammatory responses that may potentiate immunity and regulatory processes that protect the host from cytokine storms that can induce life threatening illness.

Discovery of ultrapotent broadly neutralizing antibodies from SARS-CoV-2 elite neutralizers.

A fraction of COVID-19 convalescent individuals mount a potent antibody response to SARS-CoV-2 with cross-reactivity to SARS-CoV-1. To uncover their humoral response in detail, we performed single B cell analysis from 10 SARS-CoV-2 elite neutralizers. We isolated and analyzed 126 monoclonal antibodies, many of which were sarbecovirus cross-reactive, with some displaying merbecovirus- and embecovirus-reactivity. Several isolated broadly neutralizing antibodies were effective against B.1.1.7, B.1.351, B.1.429, B.1.617, and B.1.617.2 variants and 19 prominent potential escape sites. Furthermore, assembly of 716,806 SARS-CoV-2 sequences predicted emerging escape variants, which were also effectively neutralized. One of these broadly neutralizing potent antibodies, R40-1G8, is a IGHV3-53 RBD-class-1 antibody. Remarkably, cryo-EM analysis revealed that R40-1G8 has a flexible binding mode, targeting both "up" and "down" conformations of the RBD. Given the threat of emerging SARS-CoV-2 variants, we demonstrate that elite neutralizers are a valuable source for isolating ultrapotent antibody candidates to prevent and treat SARS-CoV-2 infection.

A Dual-Antigen Enzyme-Linked Immunosorbent Assay Allows the Assessment of Severe Acute Respiratory Syndrome Coronavirus 2 Antibody Seroprevalence in a Low-Transmission Setting.

Estimates of seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies have been hampered by inadequate assay sensitivity and specificity. Using an enzyme-linked immunosorbent assay-based approach that combines data about immunoglobulin G responses to both the nucleocapsid and spike receptor binding domain antigens, we show that excellent sensitivity and specificity can be achieved. We used this assay to assess the frequency of virus-specific antibodies in a cohort of elective surgery patients in Australia and estimated seroprevalence in Australia to be 0.28% (95% Confidence Interval, 0-1.15%). These data confirm the low level of transmission of SARS-CoV-2 in Australia before July 2020 and validate the specificity of our assay.

Assessing the feasibility and appropriateness of introducing a national health insurance scheme in Malawi.

BACKGROUND: In May 2015 the Malawian Ministry of Health (MOH) contacted the German Development Cooperation to seek technical assistance from the P4H Network for Social Health Protection for an "Assessment of the appropriateness and feasibility of National Health Insurance in Malawi" against two alternative options: continuing with a tax (and donor)-funded National Health Service, and introducing a purchaser-provider split without a revenue collection function. METHODS: A health financing benchmarking matrix was agreed with MOH, with six domains corresponding to six objectives: revenue mobilisation, technical efficiency, equity, financial risk protection, policy coordination, and health outcomes. The assessment comprised key informant interviews with Malawian stakeholders, a review of the relevant literature and datasets, rapid assessments of the Malawi Revenue Authority (MRA) and the Unified Beneficiary Registry (UBR), and projections of the National Health Insurance Scheme's (NHIS) revenue collection costs and benefits. RESULTS: A key finding was that introducing NHIS in Malawi would increase revenues for health, but these would come predominantly from the formal sector and would be unlikely to cover the health sector funding gap. The performance of existing poverty identification and targeting mechanisms was not commensurate with the requirements of a NHIS. Incentives to enrol in NHI are insufficient to reach scale unless service fees be introduced, which would negatively affect equity and financial risk protection. The assessment identified the Purchaser Scenario as the most favourable reform model. CONCLUSIONS: As ever more countries look towards implementing National Health Insurance, the proposed assessment framework can provide an orientation for evidence-based policy making in the area of health financing.