Report 46: Factors driving extensive spatial and temporal fluctuations in COVID-19 fatality rates in Brazilian hospitals.

The SARS-CoV-2 Gamma variant spread rapidly across Brazil, causing substantial infection and death waves. We use individual-level patient records following hospitalisation with suspected or confirmed COVID-19 to document the extensive shocks in hospital fatality rates that followed Gamma's spread across 14 state capitals, and in which more than half of hospitalised patients died over sustained time periods. We show that extensive fluctuations in COVID-19 in-hospital fatality rates also existed prior to Gamma's detection, and were largely transient after Gamma's detection, subsiding with hospital demand. Using a Bayesian fatality rate model, we find that the geographic and temporal fluctuations in Brazil's COVID-19 in-hospital fatality rates are primarily associated with geographic inequities and shortages in healthcare capacity. We project that approximately half of Brazil's COVID-19 deaths in hospitals could have been avoided without pre-pandemic geographic inequities and without pandemic healthcare pressure. Our results suggest that investments in healthcare resources, healthcare optimization, and pandemic preparedness are critical to minimize population wide mortality and morbidity caused by highly transmissible and deadly pathogens such as SARS-CoV-2, especially in low- and middle-income countries. NOTE: The following manuscript has appeared as 'Report 46 - Factors driving extensive spatial and temporal fluctuations in COVID-19 fatality rates in Brazilian hospitals' at https://spiral.imperial.ac.uk:8443/handle/10044/1/91875 . ONE SENTENCE SUMMARY: COVID-19 in-hospital fatality rates fluctuate dramatically in Brazil, and these fluctuations are primarily associated with geographic inequities and shortages in healthcare capacity.

Global disparities in SARS-CoV-2 genomic surveillance.

Genomic sequencing provides critical information to track the evolution and spread of SARS-CoV-2, optimize molecular tests, treatments and vaccines, and guide public health responses. To investigate the spatiotemporal heterogeneity in the global SARS-CoV-2 genomic surveillance, we estimated the impact of sequencing intensity and turnaround times (TAT) on variant detection in 167 countries. Most countries submit genomes >21 days after sample collection, and 77% of low and middle income countries sequenced <0.5% of their cases. We found that sequencing at least 0.5% of the cases, with a TAT <21 days, could be a benchmark for SARS-CoV-2 genomic surveillance efforts. Socioeconomic inequalities substantially impact our ability to quickly detect SARS-CoV-2 variants, and undermine the global pandemic preparedness.

Neutralisation of SARS-CoV-2 lineage P.1 by antibodies elicited through natural SARS-CoV-2 infection or vaccination with an inactivated SARS-CoV-2 vaccine: an immunological study.

BACKGROUND: Mutations accrued by SARS-CoV-2 lineage P.1-first detected in Brazil in early January, 2021-include amino acid changes in the receptor-binding domain of the viral spike protein that also are reported in other variants of concern, including B.1.1.7 and B.1.351. We aimed to investigate whether isolates of wild-type P.1 lineage SARS-CoV-2 can escape from neutralising antibodies generated by a polyclonal immune response. METHODS: We did an immunological study to assess the neutralising effects of antibodies on lineage P.1 and lineage B isolates of SARS-CoV-2, using plasma samples from patients previously infected with or vaccinated against SARS-CoV-2. Two specimens (P.1/28 and P.1/30) containing SARS-CoV-2 lineage P.1 (as confirmed by viral genome sequencing) were obtained from nasopharyngeal and bronchoalveolar lavage samples collected from patients in Manaus, Brazil, and compared against an isolate of SARS-CoV-2 lineage B (SARS.CoV2/SP02.2020) recovered from a patient in Brazil in February, 2020. Isolates were incubated with plasma samples from 21 blood donors who had previously had COVID-19 and from a total of 53 recipients of the chemically inactivated SARS-CoV-2 vaccine CoronaVac: 18 individuals after receipt of a single dose and an additional 20 individuals (38 in total) after receipt of two doses (collected 17-38 days after the most recent dose); and 15 individuals who received two doses during the phase 3 trial of the vaccine (collected 134-230 days after the second dose). Antibody neutralisation of P.1/28, P.1/30, and B isolates by plasma samples were compared in terms of median virus neutralisation titre (VNT50, defined as the reciprocal value of the sample dilution that showed 50% protection against cytopathic effects). FINDINGS: In terms of VNT50, plasma from individuals previously infected with SARS-CoV-2 had an 8·6 times lower neutralising capacity against the P.1 isolates (median VNT50 30 [IQR <20-45] for P.1/28 and 30 [<20-40] for P.1/30) than against the lineage B isolate (260 [160-400]), with a binominal model showing significant reductions in lineage P.1 isolates compared with the lineage B isolate (p≤0·0001). Efficient neutralisation of P.1 isolates was not seen with plasma samples collected from individuals vaccinated with a first dose of CoronaVac 20-23 days earlier (VNT50s below the limit of detection [<20] for most plasma samples), a second dose 17-38 days earlier (median VNT50 24 [IQR <20-25] for P.1/28 and 28 [<20-25] for P.1/30), or a second dose 134-260 days earlier (all VNT50s below limit of detection). Median VNT50s against the lineage B isolate were 20 (IQR 20-30) after a first dose of CoronaVac 20-23 days earlier, 75 (<20-263) after a second dose 17-38 days earlier, and 20 (<20-30) after a second dose 134-260 days earlier. In plasma collected 17-38 days after a second dose of CoronaVac, neutralising capacity against both P.1 isolates was significantly decreased (p=0·0051 for P.1/28 and p=0·0336 for P.1/30) compared with that against the lineage B isolate. All data were corroborated by results obtained through plaque reduction neutralisation tests. INTERPRETATION: SARS-CoV-2 lineage P.1 might escape neutralisation by antibodies generated in response to polyclonal stimulation against previously circulating variants of SARS-CoV-2. Continuous genomic surveillance of SARS-CoV-2 combined with antibody neutralisation assays could help to guide national immunisation programmes. FUNDING: São Paulo Research Foundation, Brazilian Ministry of Science, Technology and Innovation and Funding Authority for Studies, Medical Research Council, National Council for Scientific and Technological Development, National Institutes of Health. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.

A world of cities and the end of TB.

The WHO's End TB Strategy aims to reduce TB deaths by 95% and incidence by 90% between 2015 and 2035. As the world rapidly urbanizes, more people could have access to better infrastructure and services to help combat poverty and infectious diseases, including TB. And yet large numbers of people now live in overcrowded slums, with poor access to urban health services, amplifying the burden of TB. An alignment of the Sustainable Development Goals (SDGs) for health and for urban development provides an opportunity to accelerate the overall decline in infection and disease, and to create cities free of TB.

The Global Drug Facility as an intervention in the market for tuberculosis drugs.

OBJECTIVE: To investigate funding for the Global Drug Facility since 2001 and to analyse the facility's influence on the price of high-quality tuberculosis drugs. METHODS: Data on the price of tuberculosis drugs were obtained from the Global Drug Facility for 2001 to 2012 and, for the private sector in 15 countries, from IMS Health for 2002 to 2012. Data on funding of the facility were also collected. FINDINGS: Quality-assured tuberculosis drugs supplied by the Global Drug Facility were generally priced lower than drugs purchased in the private sector. In 2012, just three manufacturers accounted for 29.9 million United Stated dollars (US$) of US$ 44.5 million by value of first-line drugs supplied. The Global Fund to Fight AIDS, Tuberculosis and Malaria provided 73% (US$ 32.5 million of US$ 44.5 million) and 89% (US$ 57.8 million of US $65.2 million) of funds for first- and second-line drugs, respectively. Between 2010 and 2012, the facility's market share of second-line tuberculosis drugs increased from 26.1% to 42.9%, while prices decreased by as much as 24% (from US$ 1231 to US$ 939). Conversely, the facility's market share of first-line drugs fell from 37.2% to 19.2% during this time, while prices increased from US$ 9.53 to US$ 10.2. CONCLUSION: The price of tuberculosis drugs supplied through the facility was generally less than that on the private market. However, to realize its full potential and meet the needs of more tuberculosis patients, the facility requires more diverse and stable public funding and greater flexibility to participate in the private market.

Creating a global observatory for health R&D.

A global map of health R&D activity would improve the coordination of research and help to match limited resources with public health priorities, such as combating antimicrobial resistance. The challenges of R&D mapping are large because there are few standards for research classification and governance and limited capacity to report on R&D data, especially in low-income countries. Nevertheless, based on developments in semantic classification, and with better reporting of funded research though the Internet, it is now becoming feasible to create a global observatory for health R&D.

After 2015: infectious diseases in a new era of health and development.

Running over timescales that span decades or centuries, the epidemiological transition provides the central narrative of global health. In this transition, a reduction in mortality is followed by a reduction in fertility, creating larger, older populations in which the main causes of illness and death are no longer acute infections of children but chronic diseases of adults. Since the year 2000, the Millennium Development Goals (MDGs) have provided a framework for accelerating the decline of infectious diseases, backed by a massive injection of foreign investment to low-income countries. Despite the successes of the MDGs era, the inhabitants of low-income countries still suffer an enormous burden of disease owing to diarrhoea, pneumonia, HIV/AIDS, tuberculosis, malaria and other pathogens. Adding to the predictable burden of endemic disease, the threat of pandemics is ever-present and global. With a view to the future, this review spotlights five aspects of the fight against infection beyond 2015, when the MDGs will be replaced by a new set of goals for poverty reduction and sustainable development. These aspects are: exploiting the biological links between infectious and non-infectious diseases; controlling infections among the new urban majority; enhancing the response to international health threats; expanding childhood immunization programmes to prevent acute and chronic diseases in adults; and working towards universal health coverage. By scanning the wider horizon now, infectious disease specialists have the chance to shape the post-2015 era of health and development.

Making wider use of the world's most widely used vaccine: Bacille Calmette-Guerin revaccination reconsidered.

Approximately 100 million newborn children receive Bacille Calmette-Guérin (BCG) annually, because vaccination is consistently protective against childhood tuberculous meningitis and miliary TB. By contrast, BCG efficacy against pulmonary TB in children and adults is highly variable, ranging from 0% to 80%, though it tends to be higher in individuals who have no detectable prior exposure to mycobacterial infections, as judged by the absence of delayed-type hypersensitivity response (a negative tuberculin skin test, TST). The duration of protection against pulmonary TB is also variable, but lasts about 10 years on average. These observations raise the possibility that BCG revaccination, following primary vaccination in infancy, could be efficacious among TST-negative adolescents as they move into adulthood, the period of highest risk for pulmonary disease. To inform continuing debate about revaccination, this paper assesses the effectiveness and cost-effectiveness of revaccinating adolescents in a setting with intense transmission-Cape Town, South Africa. For a cost of revaccination in the range US$1-10 per person, and vaccine efficacy between 10% and 80% with protection for 10 years, the incremental cost per year of healthy life recovered (disability-adjusted life years, DALY) in the vaccinated population lies between US$116 and US$9237. The intervention is about twice as cost-effective when allowing for the extra benefits of preventing transmission, with costs per DALY recovered in the range US$52-$4540. At 80% efficacy, revaccination averted 17% of cases. Under the scenarios investigated, BCG revaccination is cost-effective against international benchmarks, though not highly effective. Cost-effectiveness ratios would be more favourable if we also allow for TB cases averted by preventing transmission to HIV-positive people, for the protection of HIV-negative people who later acquire HIV infection, for the possible non-specific benefits of BCG, for the fact that some adolescents would receive BCG for the first time, and for cost sharing when BCG is integrated into an adolescent immunization programme. These findings suggest, subject to further evaluation, that BCG revaccination could be cost-effective in some settings.

The Global Drug Facility and its role in the market for tuberculosis drugs.

Universal access to high-quality treatment is central to the Global Plan to Stop TB. The Global Drug Facility (GDF) was launched in 2001 to help to achieve this goal, through services including the supply of affordable, quality-assured drugs to countries in need. We assess the scale of GDF drug supplies worldwide and find that the GDF commands a substantial proportion of the market for drugs for first-line and second-line treatment regimens, having supplied, for example, first-line drugs for roughly 35% of cases reported worldwide in 2011. Significant potential remains for GDF expansion, especially in the provision of second-line drugs, which would be aided by future increases in case detection.

National and international policies to mitigate disease threats.

To devise and implement effective health policy, we must define the problem, choose the tools, craft the policy, build consensus, set goals and deadlines, raise funds and take action. Success or failure depends on the perception of risk, the strength of the underlying science, the efficacy of the technology, ownership and intellectual property, the conflict between individual and public health, the choice of weaker (guidelines) and stronger (law) policy instruments, the level of public interest, political opportunity, institutional inertia, mechanisms for enforcement and who foots the bill. All these things considered, this paper is a brief policy-making guide by example, illustrating some achievements and disappointments with reference to cholera, drug-resistant tuberculosis, HIV/AIDS and rabies.

Evaluation of immigrant tuberculosis screening in industrialized countries.

In industrialized countries, tuberculosis (TB) cases are concentrated among immigrants and driven by reactivation of imported latent TB infection (LTBI). We examined mechanisms used to screen immigrants for TB and LTBI by sending an anonymous, 18-point questionnaire to 31 member countries of the Organisation for Economic Co-operation and Development. Twenty-nine (93.5%) of 31 responded; 25 (86.2%) screened immigrants for active TB. Fewer countries (16/29, 55.2%) screened for LTBI. Marked variations were observed in targeted populations for age (range <5 years of age to all age groups) and TB incidence in countries of origin of immigrants (>20 cases/100,000 population to >500 cases/100,000). LTBI screening was conducted in 11/16 countries by using the tuberculin skin test. Six countries used interferon-γ release assays, primarily to confirm positive tuberculin skin test results. Industrialized countries performed LTBI screening infrequently and policies varied widely. There is an urgent need to define the cost-effectiveness of LTBI screening strategies for immigrants.

Combining domestic and foreign investment to expand tuberculosis control in China.

Jia and colleagues describe how a combination of increased domestic funding, supplemented by foreign loans and donations since 2002, have led to a dramatic increase in tuberculosis case finding in China.

Lives saved by Global Fund-supported HIV/AIDS, tuberculosis and malaria programs: estimation approach and results between 2003 and end-2007.

BACKGROUND: Since 2003, the Global Fund has supported the scale-up of HIV/AIDS, tuberculosis and malaria control in low- and middle-income countries. This paper presents and discusses a methodology for estimating the lives saved through selected service deliveries reported to the Global Fund. METHODS: Global Fund-supported programs reported, by end-2007, 1.4 million HIV-infected persons on antiretroviral treatment (ARV), 3.3 million new smear-positive tuberculosis cases detected in DOTS (directly observed TB treatment, short course) programs, and 46 million insecticide-treated mosquito nets (ITNs) delivered. We estimated the corresponding lives saved using adaptations of existing epidemiological estimation models. RESULTS: By end-2007, an estimated 681,000 lives (95% uncertainty range 619,000-774,000) were saved and 1,097,000 (993,000-1,249,000) life-years gained by ARV. DOTS treatment would have saved 1.63 million lives (1.09-2.17 million) when compared against no treatment, or 408,000 lives (265,000-551,000) when compared against non-DOTS treatment. ITN distributions in countries with stable endemic falciparum malaria were estimated to have achieved protection from malaria for 26 million of child-years at risk cumulatively, resulting in 130,000 (27,000-232,000) under-5 deaths prevented. CONCLUSIONS: These results illustrate the scale of mortality effects that supported programs may have achieved in recent years, despite margins of uncertainty and covering only selected intervention components. Evidence-based evaluation of disease impact of the programs supported by the Global Fund with international and in-country partners must be strengthened using population-level data on intervention coverage and demographic outcomes, information on quality of services, and trends in disease burdens recorded in national health information systems.

Health in financial crises: economic recession and tuberculosis in Central and Eastern Europe.

The ongoing global financial crisis, which began in 2007, has drawn attention to the effect of declining economic conditions on public health. A quantitative analysis of previous events can offer insights into the potential health effects of economic decline. In the early 1990s, widespread recession across Central and Eastern Europe accompanied the collapse of the Soviet Union. At the same time, despite previously falling tuberculosis (TB) incidence in most countries, there was an upsurge of TB cases and deaths throughout the region. Here, we study the quantitative relationship between the lost economic productivity and excess TB cases and mortality. We use the data of the World Health Organization for TB notifications and deaths from 1980 to 2006, and World Bank data for gross domestic product. Comparing 15 countries for which sufficient data exist, we find strong linear associations between the lost economic productivity over the period of recession for each country and excess numbers of TB cases (r(2) = 0.94, p < 0.001) and deaths (r(2) = 0.94, p < 0.001) over the same period. If TB epidemiology and control are linked to economies in 2009 as they were in 1991 then the Baltic states, particularly Latvia, are now vulnerable to another upturn in TB cases and deaths. These projections are in accordance with emerging data on drug consumption, which indicate that these countries have undergone the greatest reductions since the beginning of 2008. We recommend close surveillance and monitoring during the current recession, especially in the Baltic states.