Making the World Safer and Fairer in Pandemics

Global health has long been characterized by injustice, with certain populations marginalized and made vulnerable by social, economic, and health disparities within and among countries. The pandemic only amplified inequalities. In response to it, the World Health Organization and the United Nations have embarked on transformative normative and financial reforms that could reimagine pandemic prevention, preparedness, and response (PPPR). These reforms include a new strategy to sustainably finance the WHO, a UN political declaration on PPPR, a fundamental revision to the International Health Regulations, and negotiation of a new, legally binding pandemic agreement (popularly called the “Pandemic Treaty”). We revisit the cavernous shortcomings of the global Covid-19 response, explain potentially transformative legal reforms and the ethical values that underpin them, and propose actionable solutions to advance both health and justice

Financing Reforms to Meet a Pivotal Moment in Global Health

2024 will be the most important moment for global health since the World Health Organization’s founding in 1948, but only if states give major reforms their full political and financial backing. Bold new commitments in disease surveillance, capacity building, and more equitable access to health products cannot be achieved without ample and sustainable funding. In this essay, we discuss major reforms found in the emerging pandemic agreement and reformed International Health Regulations and then explore the significant challenges and opportunities for financing them

Going Global, Acting Local: How an International Pandemic Convention Can Support Regional and Community Response

A WHO pandemic convention could set in place an overarching framework needed for strengthening global health security. As the World Health Assembly (WHA) debated the merits of such an agreement, a critically important regional instrument – the Treaty for the Establishment of the African Medicines Agency (AMA Treaty) – entered into force on 5 November 2021. The new agency will, among other things, ensure there is a “common framework” for addressing “emerging issues and pandemics in the event of a public health emergency on the continent with cross border or regional implications.” An improved worldwide health security strategy is essential but global mechanisms should complement without undermining effective regional, national, and sub-national approaches. Consequently, WHA decision-makers should carefully consider the scope of a potential global convention and make deliberate choices as to the content that requires truly worldwide coordination while incorporating and enhancing fit for purpose regional, national, and local strategies

No Future but a Shared Future

The COVID-19 pandemic revealed the fractured and inadequate state of national and global health law and institutions, revealing deeply embedded inequalities. In response to a World Health Assembly resolution proposing a special session to consider the benefits of developing a WHO convention or other international instrument on pandemic preparedness and response, the O’Neill Institute for National and Global Health Law and the Foundation for the National Institutes of Health (FNIH) convened 30 of the world’s leading authorities on global health law, financing, biomedical science, implementation, and emergency response along with leaders from prominent international organizations deeply engaged in responding to the pandemic. This meeting was followed by regional consultations convened in Africa, Latin America-Caribbean, and Southeast Asia. The O’Neill Institute/FNIH also held a consultation with civil society representatives. This article is a concise, edited excerpt of the report of those meetings, outlining the options for such an international instrument

Financing the future of WHO

WHO\u27s resources have consistently lagged behind its constitutional mandate. There is a deep misalignment between what governments and the public expect WHO to do and what the organisation is resourced to do. WHO is challenged by low levels of political will to increase its financing, strained government treasuries, and a battle over control of priorities. WHO\u27s Executive Board has charged the Working Group on Sustainable Financing with identifying a viable plan for sustainable financing before the World Health Assembly in May. There is no time to lose. WHO\u27s resourcing strategy must match its mission with assured financial support from member states buttressed by proven, innovative financing methods. By defining its priorities, delivering on them, and being transparent and accountable, WHO can more boldly pursue its public health mission

Advancing Equity In The Pandemic Treaty

There is a broad consensus around equity’s importance. Even countries that hoarded supplies during the acute phase of COVID-19 seem to understand that the international community must find a means to ensure fairer allocation of medical resources when the next health crisis hits. But there has been little agreement about the concrete steps needed to operationalize fairer access and benefit sharing. That is, what are the workable mechanisms that could reduce the divide between richer and poorer populations? The World Health Assembly, the governing body of the World Health Organization, has appointed an Intergovernmental Negotiating Body to develop a pandemic convention, agreement, or other instrument under the WHO constitution. The February 2023 draft is designed “to achieve greater equity … through the fullest national and international cooperation.” It is important that the negotiators develop specific, measurable metrics that directly impact equity. The mechanisms and metrics agreed upon should allow the public to evaluate whether a more equitable system is emerging through this new regime. Equity won’t just happen. We need to plan and prepare for equity, and we need international norms with which nations must comply to achieve the fairness we strive for

Structure of the first representative of Pfam family PF04016 (DUF364) reveals enolase and Rossmann-like folds that combine to form a unique active site with a possible role in heavy-metal chelation.

The crystal structure of Dhaf4260 from Desulfitobacterium hafniense DCB-2 was determined by single-wavelength anomalous diffraction (SAD) to a resolution of 2.01 Å using the semi-automated high-throughput pipeline of the Joint Center for Structural Genomics (JCSG) as part of the NIGMS Protein Structure Initiative (PSI). This protein structure is the first representative of the PF04016 (DUF364) Pfam family and reveals a novel combination of two well known domains (an enolase N-terminal-like fold followed by a Rossmann-like domain). Structural and bioinformatic analyses reveal partial similarities to Rossmann-like methyltransferases, with residues from the enolase-like fold combining to form a unique active site that is likely to be involved in the condensation or hydrolysis of molecules implicated in the synthesis of flavins, pterins or other siderophores. The genome context of Dhaf4260 and homologs additionally supports a role in heavy-metal chelation

Structure of a putative NTP pyrophosphohydrolase: YP_001813558.1 from Exiguobacterium sibiricum 255-15.

The crystal structure of a putative NTPase, YP_001813558.1 from Exiguobacterium sibiricum 255-15 (PF09934, DUF2166) was determined to 1.78 Å resolution. YP_001813558.1 and its homologs (dimeric dUTPases, MazG proteins and HisE-encoded phosphoribosyl ATP pyrophosphohydrolases) form a superfamily of all-α-helical NTP pyrophosphatases. In dimeric dUTPase-like proteins, a central four-helix bundle forms the active site. However, in YP_001813558.1, an unexpected intertwined swapping of two of the helices that compose the conserved helix bundle results in a `linked dimer' that has not previously been observed for this family. Interestingly, despite this novel mode of dimerization, the metal-binding site for divalent cations, such as magnesium, that are essential for NTPase activity is still conserved. Furthermore, the active-site residues that are involved in sugar binding of the NTPs are also conserved when compared with other α-helical NTPases, but those that recognize the nucleotide bases are not conserved, suggesting a different substrate specificity

Structure of the γ-D-glutamyl-L-diamino acid endopeptidase YkfC from Bacillus cereus in complex with L-Ala-γ-D-Glu: insights into substrate recognition by NlpC/P60 cysteine peptidases.

Dipeptidyl-peptidase VI from Bacillus sphaericus and YkfC from Bacillus subtilis have both previously been characterized as highly specific γ-D-glutamyl-L-diamino acid endopeptidases. The crystal structure of a YkfC ortholog from Bacillus cereus (BcYkfC) at 1.8 Å resolution revealed that it contains two N-terminal bacterial SH3 (SH3b) domains in addition to the C-terminal catalytic NlpC/P60 domain that is ubiquitous in the very large family of cell-wall-related cysteine peptidases. A bound reaction product (L-Ala-γ-D-Glu) enabled the identification of conserved sequence and structural signatures for recognition of L-Ala and γ-D-Glu and, therefore, provides a clear framework for understanding the substrate specificity observed in dipeptidyl-peptidase VI, YkfC and other NlpC/P60 domains in general. The first SH3b domain plays an important role in defining substrate specificity by contributing to the formation of the active site, such that only murein peptides with a free N-terminal alanine are allowed. A conserved tyrosine in the SH3b domain of the YkfC subfamily is correlated with the presence of a conserved acidic residue in the NlpC/P60 domain and both residues interact with the free amine group of the alanine. This structural feature allows the definition of a subfamily of NlpC/P60 enzymes with the same N-terminal substrate requirements, including a previously characterized cyanobacterial L-alanine-γ-D-glutamate endopeptidase that contains the two key components (an NlpC/P60 domain attached to an SH3b domain) for assembly of a YkfC-like active site

The structure of BVU2987 from Bacteroides vulgatus reveals a superfamily of bacterial periplasmic proteins with possible inhibitory function.

Proteins that contain the DUF2874 domain constitute a new Pfam family PF11396. Members of this family have predominantly been identified in microbes found in the human gut and oral cavity. The crystal structure of one member of this family, BVU2987 from Bacteroides vulgatus, has been determined, revealing a β-lactamase inhibitor protein-like structure with a tandem repeat of domains. Sequence analysis and structural comparisons reveal that BVU2987 and other DUF2874 proteins are related to β-lactamase inhibitor protein, PepSY and SmpA_OmlA proteins and hence are likely to function as inhibitory proteins