Global Outbreak Alert and Response Network deployments during the COVID-19 pandemic, WHO Western Pacific Region.

Problem: The Global Outbreak Alert and Response Network (GOARN) has responded to more than 100 outbreaks during the past 23 years. The coronavirus disease (COVID-19) pandemic presented unprecedented operational constraints that challenged GOARN's core mission to rapidly deploy technical experts from its partners to support national in-country responses to public health emergencies. This paper describes the type and duration of GOARN deployments to and within the World Health Organization's (WHO's) Western Pacific Region during the COVID-19 pandemic. Context: Despite strict border closures and ever-changing vaccination and quarantine requirements, GOARN continued to deploy international technical assistance to strengthen COVID-19 response operations within the Region, as requested. Action: Data were analysed from the GOARN Knowledge Platform about deployments to and within the Region for responses to the COVID-19 pandemic between 1 January 2020 and 5 May 2023. Data were available about deployment duration, technical role requested, country or area, partner organization and deployed expert's demographics. Feedback from postdeployment briefings with the experts was collected and thematically analysed to determine ongoing needs and gaps to help improve deployment operations. Outcome: There were 72 experts deployed on 89 missions through GOARN to 12 countries and areas in the Region, for a total of 4558 field days, to support the response to the COVID-19 pandemic. Discussion: The volume of requests for assistance from countries and areas in the Region to respond to the COVID-19 pandemic uncovered a deficit in human resources available for domestic response to outbreaks and the reliance on international assistance. Strengthening the in-country capacity of ready-to-respond public health emergency staff is critical to meet the needs for outbreak response. The ongoing demand for technical experts to support national responses means that these lessons may have immediate implications.

Developing a partnership to improve health care delivery to children <18 years with cancer and blood disorders in the English-speaking Caribbean: lessons from the SickKids-Caribbean Initiative (SCI).

In 2013, the SickKids-Caribbean Initiative (SCI) was formalised among The Hospital for Sick Children in Toronto, Canada, the University of the West Indies, and Ministries of Health in six Caribbean countries (Barbados, The Bahamas, Jamaica, St. Lucia, St. Vincent and the Grenadines, and Trinidad and Tobago). The aim was to improve the outcomes and quality of life of children (<18 years) with cancer and blood disorders in the partner countries. Core activities included filling a human resource gap by training paediatric haematologists/oncologists and specialised registered nurses; improving capacity to diagnose and treat diverse haematology/oncology cases; developing and maintaining paediatric oncology databases; creating ongoing advocacy activities with international agencies, decision makers, and civil society; and establishing an integrated administration, management, and funding structure. We describe core program components, successes, and challenges to inform others seeking to improve health service delivery in a multidisciplinary and complex partnership.

Lack of immunogenicity of xenogeneic DNA from porcine biomaterials.

Background: Clinically useful biomaterials are derived from xenogeneic extracellular matrices, but extensive processes often used to remove all residual DNA are detrimental to their proper biological function. We hypothesized that deliberate and repeated injection of DNA extracted from clinically implantable, xenogeneic extracellular matrices might elicit an immune response in a well-established murine model that could ultimately lead to altered extracellular matrix remodeling. Methods: DNA was purified from unprocessed porcine extracellular matrices and processed extracellular matrices before sterilization (aseptic) and after sterilization. Groups of 10 mice were injected with these 3 purified DNAs and 3 controls: (1) DNA from E. coli; (2) DNA from unprocessed porcine extracellular matrices combined with interleukin-12 and methylated bovine serum albumin and emulsified in incomplete Freund's adjuvant; and (3) buffered saline. Immunizations occurred every 2 weeks for a total of 3 injections. Local cytokines and systemic anti-DNA antibodies were quantified 3 and 7 days after final injection. Results: The DNA extracted from unprocessed, aseptic, or sterilized porcine extracellular matrices failed to elicit a rejection response, and only with significant, proinflammatory adjuvant activation could such a response be seen. Without the adjuvants, biomaterial-derived DNA resulted in a mild accommodation cytokine response locally and no systemic anti-DNA antibody expression even at doses approximately 100-fold larger than would be clinically likely via extracellular matrix implantation. Conclusion: The immunological safety of porcine extracellular matrix biomaterials appears not to be related to DNA residues present. Such biomaterials need not be extensively processed, likely leading to detrimental changes in their bioactivity, solely in an effort to remove the mammalian DNA.

Lethal synergy between SARS-CoV-2 and Streptococcus pneumoniae in hACE2 mice and protective efficacy of vaccination.

Secondary infections are frequent complications of viral respiratory infections, but the potential consequence of SARS-CoV-2 coinfection with common pulmonary pathogens is poorly understood. We report that coinfection of human ACE2-transgenic mice with sublethal doses of SARS-CoV-2 and Streptococcus pneumoniae results in synergistic lung inflammation and lethality. Mortality was observed regardless of whether SARS-CoV-2 challenge occurred before or after establishment of sublethal pneumococcal infection. Increased bacterial levels following coinfection were associated with alveolar macrophage depletion, and treatment with murine GM-CSF reduced numbers of lung bacteria and pathology and partially protected from death. However, therapeutic targeting of IFNs, an approach that is effective against influenza coinfections, failed to increase survival. Combined vaccination against both SARS-CoV-2 and pneumococci resulted in 100% protection against subsequent coinfection. The results indicate that when seasonal respiratory infections return to prepandemic levels, they could lead to an increased incidence of lethal COVID-19 superinfections, especially among the unvaccinated population.

Viral PB1-F2 and host IFN-γ guide ILC2 and T cell activity during influenza virus infection.

Functional plasticity of innate lymphoid cells (ILCs) and T cells is regulated by host environmental cues, but the influence of pathogen-derived virulence factors has not been described. We now report the interplay between host interferon (IFN)-γ and viral PB1-F2 virulence protein in regulating the functions of ILC2s and T cells that lead to recovery from influenza virus infection of mice. In the absence of IFN-γ, lung ILC2s from mice challenged with the A/California/04/2009 (CA04) H1N1 virus, containing nonfunctional viral PB1-F2, initiated a robust IL-5 response, which also led to improved tissue integrity and increased survival. Conversely, challenge with Puerto Rico/8/1934 (PR8) H1N1 virus expressing fully functional PB1-F2, suppressed IL-5+ ILC2 responses, and induced a dominant IL-13+ CD8 T cell response, regardless of host IFN-γ expression. IFN-γ-deficient mice had increased survival and improved tissue integrity following challenge with lethal doses of CA04, but not PR8 virus, and increased resistance was dependent on the presence of IFN-γR+ ILC2s. Reverse-engineered influenza viruses differing in functional PB1-F2 activity induced ILC2 and T cell phenotypes similar to the PB1-F2 donor strains, demonstrating the potent role of viral PB1-F2 in host resistance. These results show the ability of a pathogen virulence factor together with host IFN-γ to regulate protective pulmonary immunity during influenza infection.

Ready to respond: adapting rapid response team training in Papua New Guinea during the COVID-19 pandemic.

Problem: Rapid response teams (RRTs) are critical for effective responses to acute public health events. While validated training packages and guidance on rolling out training for RRTs are available, they lack country-specific adaptations. Documentation is limited on RRT programming experiences in various contexts. Context: In Papua New Guinea, there remain gaps in implementing standardized, rapid mobilization of multidisciplinary RRTs at the national, provincial and district levels to investigate public health alerts. Action: The human resources needed to respond to the coronavirus disease (COVID-19) pandemic forced a review of the RRT training programme and its delivery. The training model was contextualized and adapted for implementation using a staged approach, with the initiation training phase designed to ensure RRT readiness to deploy immediately in response to COVID-19 and other public health events. Lessons learned: Selecting appropriate trainees and using a phased training approach, incorporating after-training reviews, and between-phase support from the national programme team were found to be important for programme design in Papua New Guinea. Using participatory training methods based on principles of adult learning, in which trainees draw on their own experiences, was integral to building confidence among team members in conducting outbreak investigations. Discussion: The RRT training experience in Papua New Guinea has highlighted the importance of codeveloping and delivering a context-specific training programme to meet a country's unique needs. A staged training approach that builds on knowledge and skills over time, used together with ongoing follow-up and support in the provinces, has been critical in operationalizing ready-to-respond RRTs.

Determinants of access to childhood cancer medicines: a comparative, mixed-methods analysis of four Caribbean countries.

BACKGROUND: Equitable access to essential medicines is a key facet of childhood cancer care, recognised by WHO as vital to improved childhood cancer outcomes globally. In the Caribbean, childhood cancer outcomes are poorer than those in most high-income countries. We aimed to generate in-depth comparative evidence of the current challenges and opportunities related to access to childhood cancer medicines in the Caribbean to identify context-sensitive health systems strategies to improve drug access and inform evidence-based paediatric cancer policies in the region. METHODS: In this convergent, parallel, mixed-methods study, we mapped and analysed the determinants of access to childhood cancer medicines in four Caribbean countries (The Bahamas, Barbados, Jamaica, and Trinidad and Tobago). We analysed contextual determinants of access to medicines within and across study site jurisdictions, alignment of childhood cancer medicine inclusion between each country's national essential medicines list (NEML) and WHO's 2017 Essential Medicines List for Children, and availability and cost of chemotherapeutic agents at five tertiary care hospitals. We used a mixed-effects logistic regression model to analyse the association of medicine price, procurement efficiency (via median price ratio [MPR]), and site with drug availability. The fixed effect evaluated the effect of site and MPR on the probability of stockout in a given month. We assessed determinants of medicine access via thematic analysis of semi-structured qualitative interviews, literature, and policy documents. FINDINGS: We collected and analysed data for 28 childhood cancer medicines from Barbados, 32 from The Bahamas, 30 from Trinidad and Tobago, and 31 from Jamaica. Despite stepwise inclusion of childhood cancer medicines in NEMLs, all four countries had frequent and recurrent stockouts for many cytotoxic medicines, showing no consistent relationship between NEML inclusion and availability. A mean MPR of greater than 3·0 in Trinidad and Tobago, The Bahamas, and Barbados suggests uniformly high procurement inefficiency, resulting in significant effects on drug stockout days. For each one unit increase in MPR the adjusted odds ratio (OR) of stockout increased by 10% (adjusted OR 1·10, 95% CI 1·04-1·16; p<0·01). These challenges in access to childhood cancer medicines stem from health system and policy dynamics at institutional, national, and supranational levels that cause price volatility and erratic medicine availability. Key challenges include disparate policy commitments (eg, among sites), inefficient procurement and supply chain management practices, and local effects of international market pressures. INTERPRETATION: The Caribbean region exemplifies deficiencies in access to childhood cancer medicines that might be overcome by improved regional harmonisation of drug registration, pharmacovigilance, and procurement alongside national forecasting to strengthen global pharmaceutical planning and prioritisation. Focused political attention to address these challenges is required to ensure efficient, reliable, and sustained availability of cancer mediciness. FUNDING: The SickKids-Caribbean Initiative.

Ward-level factors associated with methicillin-resistant Staphylococcus aureus acquisition-an electronic medical records study in Singapore.

BACKGROUND: Methicillin-Resistant Staphylococcus aureus (MRSA) is endemic in hospitals worldwide. Intrahospital transfers may impact MRSA acquisition risk experienced by patients. In this study, we investigated ward characteristics and connectivity that are associated with MRSA acquisition. METHODS: We analysed electronic medical records on patient transfers and MRSA screening of in-patients at an acute-care tertiary hospital in Singapore to investigate whether ward characteristics and connectivity within a network of in-patient wards were associated with MRSA acquisition rates over a period of four years. RESULTS: Most patient transfers concentrated in a stable core network of wards. Factors associated with increased rate of MRSA acquisition were MRSA prevalence among patients transferred from other wards (rate ratio (RR): 7.74 [95% confidence interval (CI): 3.88, 15.44], additional 5 percentage point), critical care ward (RR: 1.72 [95% CI: 1.09, 2.70]) and presence of MRSA cohorting beds (RR: 1.39 [95% CI: 1.03, 1.90]. Oncology ward (RR: 0.66 [95% CI: 0.46, 0.94]) (compared to medical ward), and median length of stay (RR: 0.70 [95% CI: 0.55, 0.90], additional 1.5 days) were associated with lower acquisition rates. In addition, we found evidence of interaction between MRSA prevalence among patients transferred from other wards and weighted in-degree although the latter was not associated with MRSA acquisition after controlling for confounders. CONCLUSION: Wards with higher MRSA prevalence among patients transferred from other wards were more likely to have higher MRSA acquisition rate. Its effect further increased in wards receiving greater number of patients. In addition, critical care ward, presence of MRSA cohorting beds, ward specialty, and median length of stay were associated with MRSA acquisition.

Training for outbreak response through the Global Outbreak Alert and Response Network.

For 20 years, the Global Outbreak Response and Alert Network (GOARN) has been a leader in the coordination of international outbreak response. On the premise that no single institution can provide all capacities required to successfully respond to a complex public health emergency or fulfil all outbreak response training needs, GOARN embarked on a capacity building journey that draws on the unique strengths of more than 250 partner institutions. Through extensive engagement and collaboration, GOARN Partners have created a bespoke, multifaceted, 3-tiered training programme which has evolved over the last 15 years and enhanced the competencies of thousands of multidisciplinary outbreak responders around the world.

Sequential targeting of interferon pathways for increased host resistance to bacterial superinfection during influenza.

Bacterial co-infections represent a major clinical complication of influenza. Host-derived interferon (IFN) increases susceptibility to bacterial infections following influenza, but the relative roles of type-I versus type-II IFN remain poorly understood. We have used novel mouse models of co-infection in which colonizing pneumococci were inoculated into the upper respiratory tract; subsequent sublethal influenza virus infection caused the bacteria to enter the lungs and mediate lethal disease. Compared to wild-type mice or mice deficient in only one pathway, mice lacking both IFN pathways demonstrated the least amount of lung tissue damage and mortality following pneumococcal-influenza virus superinfection. Therapeutic neutralization of both type-I and type-II IFN pathways similarly provided optimal protection to co-infected wild-type mice. The most effective treatment regimen was staggered neutralization of the type-I IFN pathway early during co-infection combined with later neutralization of type-II IFN, which was consistent with the expression and reported activities of these IFNs during superinfection. These results are the first to directly compare the activities of type-I and type-II IFN during superinfection and provide new insights into potential host-directed targets for treatment of secondary bacterial infections during influenza.

SON DNA-binding protein mediates macrophage autophagy and responses to intracellular infection.

Intracellular pathogens affect diverse host cellular defence and metabolic pathways. Here, we used infection with Francisella tularensis to identify SON DNA-binding protein as a central determinant of macrophage activities. RNAi knockdown of SON increases survival of human macrophages following F. tularensis infection or inflammasome stimulation. SON is required for macrophage autophagy, interferon response factor 3 expression, type I interferon response and inflammasome-associated readouts. SON knockdown has gene- and stimulus-specific effects on inflammatory gene expression. SON is required for accurate splicing and expression of GBF1, a key mediator of cis-Golgi structure and function. Chemical GBF1 inhibition has similar effects to SON knockdown, suggesting that SON controls macrophage functions at least in part by controlling Golgi-associated processes.

Evaluation of Pneumococcal Surface Protein A as a Vaccine Antigen against Secondary Streptococcus pneumoniae Challenge during Influenza A Infection.

Secondary bacterial pneumonia is responsible for significant morbidity and mortality during seasonal and pandemic influenza. Due to the unpredictability of influenza A virus evolution and the time-consuming process of manufacturing strain-specific influenza vaccines, recent efforts have been focused on developing anti-Streptococcus pneumoniae immunity to prevent influenza-related illness and death. Bacterial vaccination to prevent viral-bacterial synergistic interaction during co-infection is a promising concept that needs further investigation. Here, we show that immunization with pneumococcal surface protein A (PspA) fully protects mice against low-dose, but not high-dose, secondary bacterial challenge using a murine model of influenza A virus-S. pneumoniae co-infection. We further show that immunization with PspA is more broadly protective than the pneumococcal conjugate vaccine (Prevnar). These results demonstrate that PspA is a promising vaccine target that can provide protection against a physiologically relevant dose of S. pneumoniae following influenza infection.

Allergic Airway Disease Prevents Lethal Synergy of Influenza A Virus-Streptococcus pneumoniae Coinfection.

Fatal outcomes following influenza infection are often associated with secondary bacterial infections. Allergic airway disease (AAD) is known to influence severe complications from respiratory infections, and yet the mechanistic effect of AAD on influenza virus-Streptococcus pneumoniae coinfection has not been investigated previously. We examined the impact of AAD on host susceptibility to viral-bacterial coinfections. We report that AAD improved survival during coinfection when viral-bacterial challenge occurred 1 week after AAD. Counterintuitively, mice with AAD had significantly deceased proinflammatory responses during infection. Specifically, both CD4+ and CD8+ T cell interferon gamma (IFN-γ) responses were suppressed following AAD. Resistance to coinfection was also associated with strong transforming growth factor ß1 (TGF-ß1) expression and increased bacterial clearance. Treatment of AAD mice with IFN-γ or genetic deletion of TGF-ß receptor II expression reversed the protective effects of AAD. Using a novel triple-challenge model system, we show for the first time that AAD can provide protection against influenza virus-S. pneumoniae coinfection through the production of TGF-ß that suppresses the influenza virus-induced IFN-γ response, thereby preserving antibacterial immunity.IMPORTANCE Asthma has become one of the most common chronic diseases and has been identified as a risk factor for developing influenza. However, the impact of asthma on postinfluenza secondary bacterial infection is currently not known. Here, we developed a novel triple-challenge model of allergic airway disease, primary influenza infection, and secondary Streptococcus pneumoniae infection to investigate the impact of asthma on susceptibility to viral-bacterial coinfections. We report for the first time that mice recovering from acute allergic airway disease are highly resistant to influenza-pneumococcal coinfection and that this resistance is due to inhibition of influenza virus-mediated impairment of bacterial clearance. Further characterization of allergic airway disease-associated resistance against postinfluenza secondary bacterial infection may aid in the development of prophylactic and/or therapeutic treatment against coinfection.

Topical application of nebulized human IgG, IgA and IgAM in the lungs of rats and non-human primates.

BACKGROUND: Recurrent and persistent infections are known to affect airways of patients with Primary Immunodeficiency despite appropriate replacement immunoglobulin serum levels. Interestingly, patients with Chronic Obstructive Pulmonary Disease or with non-CF bronchiectasis also show similar susceptibility to such infections. This may be due to the limited availability of immunoglobulins from the systemic circulation in the conductive airways, resulting in local immunodeficiency. Topical application of nebulized plasma-derived immunoglobulins may represent a means to address this deficiency. In this study, we assessed the feasibility of nebulizing plasma-derived immunoglobulins and delivering them into the airways of rats and non-human primates. METHODS: Distinct human plasma-derived immunoglobulin isotype preparations were nebulized with an investigational eFlow® nebulizer and analyzed in vitro or deposited into animals. Biochemical and immunohistological analysis of nebulized immunoglobulins were then performed. Lastly, efficacy of topically applied human plasma-derived immunoglobulins was assessed in an acute Streptococcus pneumoniae respiratory infection in mice. RESULTS: Characteristics of the resulting aerosols were comparable between preparations, even when using solutions with elevated viscosity. Neither the structural integrity nor the biological function of nebulized immunoglobulins were compromised by the nebulization process. In animal studies, immunoglobulins levels were assessed in plasma, broncho-alveolar lavages (BAL) and on lung sections of rats and non-human primates in samples collected up to 72 h following application. Nebulized immunoglobulins were detectable over 48 h in the BAL samples and up to 72 h on lung sections. Immunoglobulins recovered from BAL fluid up to 24 h after inhalation remained structurally and functionally intact. Importantly, topical application of human plasma-derived immunoglobulin G into the airways of mice offered significant protection against acute pneumococcal pneumonia. CONCLUSION: Taken together our data demonstrate the feasibility of topically applying plasma-derived immunoglobulins into the lungs using a nebulized liquid formulation. Moreover, topically administered human plasma-derived immunoglobulins prevented acute respiratory infection.

Defective anti-polysaccharide IgG vaccine responses in IgA deficient mice.

We report that IgA-/- mice exhibit specific defects in IgG antibody responses to various polysaccharide vaccines (Francisella tularensis LPS and Pneumovax), but not protein vaccines such as Fluzone. This defect further included responses to polysaccharide-protein conjugate vaccines (Prevnar and Haemophilus influenzae type b-tetanus toxoid vaccine). In agreement with these findings, IgA-/- mice were protected from pathogen challenge with protein- but not polysaccharide-based vaccines. Interestingly, after immunization with live bacteria, IgA+/+ and IgA-/- mice were both resistant to lethal challenge and their IgG anti-polysaccharide antibody responses were comparable. Immunization with live bacteria, but not purified polysaccharide, induced production of serum B cell-activating factor (BAFF), a cytokine important for IgG class switching; supplementing IgA-/- cell cultures with BAFF enhanced in vitro polyclonal IgG production. Taken together, these findings show that IgA deficiency impairs IgG class switching following vaccination with polysaccharide antigens and that live bacterial immunization can overcome this defect. Since IgA deficient patients also often show defects in antibody responses following immunization with polysaccharide vaccines, our findings could have relevance to the clinical management of this population.

Residency Training at the Front of the West African Ebola Outbreak: Adapting for a Rare Opportunity.

Medical trainees face multiple barriers to participation in major outbreak responses such as that required for Ebola Virus Disease through 2014-2015 in West Africa. Hurdles include fear of contracting and importing the disease, residency requirements, scheduling conflicts, family obligations and lack of experience and maturity. We describe the successful four-week deployment to Liberia of a first year infectious diseases trainee through the mechanism of the Global Outbreak Alert and Response Network of the World Health Organization. The posting received prospective approval from the residency supervisory committees and employing hospital management and was designed with components fulfilling the Accreditation Council for Graduate Medical Education (ACGME) core competencies. It mirrored conventional training with regards to learning objectives, supervisory framework and assessment methods. Together with Centers for Disease Control and Prevention and many other partners, the team joined the infection prevention and control efforts in Monrovia. Contributions were made to a 'ring fencing' infection control approach that was being introduced, including enhancement of triage, training and providing supplies in high priority health-care facilities in the capital and border zones. In addition the fellow produced an electronic database that enabled monitoring infection control standards in health facilities. This successful elective posting illustrates that quality training can be achieved, even in the most challenging environments, with support from the pedagogic and sponsoring institutions. Such experiential learning opportunities benefit both the outbreak response and the trainee, and if scaled up would contribute towards building a global health emergency workforce. More should be done from residency accreditation bodies in facilitating postings in outbreak settings.