Transdisciplinary research before, during and after COVID-19 vaccination in Chile: a virtuoso collaboration with future perspectives.

The COVID-19 pandemic presented numerous challenges that required immediate attention to mitigate its devastating consequences on a local and global scale. In March 2020, the Chilean government, along with health and science authorities, implemented a strategy aimed at generating relevant evidence to inform effective public health decisions. One of the key strengths of this strategy was the active involvement of the scientific community, employing transdisciplinary approaches to address critical questions and support political decision-making. The strategy promoted collaborations between the government, public and private institutions, and transdisciplinary academic groups throughout each phase of the pandemic. By focusing on pressing problems and questions, this approach formed the foundation of this report which reflects the collaborative effort throughout the pandemic of individuals from the Instituto de Sistemas Complejos de Ingeniería (ISCI), the Faculty of Medicine of the University of Chile, government authorities and industry. Early in the pandemic, it became crucial to gather evidence on how to minimize the impact of infection and disease while awaiting the availability of vaccines. This included studying the dynamics of SARS-CoV-2 infection in children, assessing the impact of quarantines on people's mobility, implementing strategies for widespread SARS-CoV-2 polymerase chain reaction (PCR) testing, and exploring pool testing for large populations. The urgent need to reduce disease severity and transmission posed a significant challenge, as it was essential to prevent overwhelming healthcare systems. Studies were conducted to predict ICU bed requirements at the local level using mathematical models. Additionally, novel approaches, such as using cellphone mobility-based technology to actively identify infected individuals, and to optimize population sampling, were explored following the first wave of the pandemic. Chile took early action in addressing vaccination through a high-level scientific board, before vaccines became available. Studies conducted during this period included population-based immunologic evaluations of different vaccines, which helped build confidence in the population and supported the need for booster doses and potential vaccination of children. These studies and collaborations, which will be discussed here, have provided valuable insights and will inform future approaches in a post-pandemic world. Importantly, highly conservative estimates indicate that 3,000 lives and more than 300 million USD were saved by this academic-public-private collaborative effort.

Impact of homologous and heterologous boosters in neutralizing antibodies titers against SARS-CoV-2 Omicron in solid-organ transplant recipients.

Introduction: Booster doses of SARS-CoV-2 vaccines improve seroconversion rates in solid organ transplant recipients (SOTRs) but the impact of homologous and heterologous booster doses in neutralizing antibody (NAb) titers and their ability to interfere with the variant of concern Omicron are not well studied. Methods: We designed a prospective, open-label, observational clinical cohort study. 45 participants received two doses of BNT162b2 or CoronaVac (21-day or 28-day intervals, respectively) followed by a first and second booster with BNT162b2 (5-month apart each) and we analyzed the neutralizing antibody titers against SARSCoV-2 D614G (B.1 lineage) and Omicron (BA.1 lineage). Results: Our results show that SOTRs receiving an initial two-dose scheme of CoronaVac or BNT162b2 generate lower NAbs titers against the ancestral variant of SARS-CoV-2 when compared with healthy controls. Although these NAb titers were further decreased against the SARS-CoV-2 Omicron, a single BNT162b2 booster in both groups was sufficient to increase NAb titers against the variant of concern. More importantly, this effect was only observed in those participants responding to the first two shots but not in those not responding to the initial vaccination scheme. Discussion: The data provided here demonstrate the importance of monitoring antibody responses in immunocompromised subjects when planning booster vaccination programs in this risk group.

Infection with SARS-CoV-2 variant Gamma (P.1) in Chile increased ICU admission risk three to five-fold.

The 2021 wave of SARS-CoV-2 infection in Chile was characterized by an explosive increase in ICU admissions, which disproportionately affected individuals younger than 60 years. This second wave was also accompanied by an explosive increase in Gamma (P.1) variant detections and the massive vaccine rollout. We unveil the role the Gamma variant played in stressing the use of critical care, by developing and calibrating a queueing model that uses data on new onset cases and actual ICU occupancy, symptom's onset to ICU admission interval, ICU length-of-stay, genomic surveillance, and vaccine effectiveness. Our model shows that infection with the Gamma (P.1) variant led to a 3.5-4.7-fold increase in ICU admission for people younger than 60 years. This situation occurred on top of the already reported higher infection rate of the Gamma variant. Importantly, our results also strongly suggest that the vaccines used in Chile (inactivated mostly, but also an mRNA), were able to curb Gamma variant ICU admission over infections.

COVID-19 lateral flow IgG seropositivity and serum neutralising antibody responses after primary and booster vaccinations in Chile: a cross-sectional study.

BACKGROUND: By June 30, 2022, 92·6% of the Chilean population older than 18 years had received a full primary SARS-CoV-2 vaccine series, mostly with CoronaVac (Sinovac Biotech), and 78·4% had received a booster dose, mostly heterologous with BNT162b2 (Pfizer-BioNTech) and ChAdOx1 (AstraZeneca). We previously reported national seroprevalence data from lateral flow testing of IgG SARS-CoV-2 antibodies up to 16 weeks after primary vaccination. Our aim here was to study IgG seropositivity dynamics up to 30 weeks after primary vaccination and, in CoronaVac recipients, up to 26 weeks after booster vaccination, and to establish the correlation between lateral flow tests and neutralising antibody titres. METHODS: In this cross-sectional study, testing stations for SARS-CoV-2 IgG detection were selected and installed from March 12, 2021, in hotspots in 24 large Chilean cities, and were maintained until March 31, 2022. Individuals voluntarily approaching the testing stations were invited to perform a rapid lateral flow test via a finger prick and complete a questionnaire. Between Aug 12, 2021, and April 1, 2022, volunteers seeking medical care in the Mutual de Seguridad de la Cámara Chilena de la Construcción provided blood samples for lateral flow testing and neutralising antibody studies; inclusion criteria were age at least 18 years, history of complete primary vaccination series with CoronaVac, BNT162b2, or ChAdOx1, or no vaccine, and no previous COVID-19 diagnosis. We tested the difference in IgG positivity across time, and between primary and booster doses, in all eligible participants with complete records, controlling for age, gender, and comorbidities. We also assessed the predictive power of neutralising antibody titres and sociodemographic characteristics on the probability of IgG positive results using multivariable logistic regression. FINDINGS: Of 107 220 individuals recruited at the testing stations, 101 070 were included in our analysis (59 862 [59·2%] women and 41 208 [40·8%] men). 65 902 (65·2%) received primary vaccination series with CoronaVac, 18 548 (18·4%) with BNT162b2, and 606 (0·6%) with ChAdOx1, and 16 014 (15·8%) received no vaccine. Among the 61 767 individuals with a complete primary vaccination series with CoronaVac, 608 (1·0%) received a CoronaVac booster, 10 095 (16·3%) received a BNT162b2 booster, and 5435 (8·8%) received a ChAdOx1 booster. After ChAdOx1 primary vaccination, seropositivity peaked at week 5 after the second dose, occurring in 13 (92·9%, 95% CI 79·4-100·0) of 14 individuals. In participants who received a complete CoronaVac primary series, the decline in seropositivity stabilised at week 18 after the second dose (86 [44·7%, 95% CI 41·8-47·7] of 1087 individuals), whereas after receiving BNT162b2, seropositivity declined slightly by week 25 after the second dose (161 [94·2%, 90·6-97·7] of 171). A lower proportion of individuals who received the CoronaVac primary series and a homologous booster were seropositive (279 [85·6%, 95% CI 81·8-89·4] of 326) by weeks 2-18 than those who received a BNT162b2 booster (7031 [98·6%, 98·4-98·9] of 7128) or a ChAdOx1 booster (2893 [98·0%, 97·5-98·5] of 2953). The correlation between IgG positivity and log of the infectious dose in 50% of neutralising antibodies was moderate, with a sensitivity of 81·4% (95% CI 76·3-86·6) and specificity of 92·5% (73·3-100·0). INTERPRETATION: Dynamic monitoring of IgG positivity to SARS-CoV-2 can characterise antibody waning over time in the absence or presence of booster doses, providing relevant data for the design of vaccination strategies. The correlation between lateral flow test IgG titres and neutralising antibody concentrations suggests that they could be a quick and effective surveillance tool to measure protection against SARS-CoV-2. FUNDING: Instituto Sistemas Complejos de Ingeniería, Subsecretaría de Redes Asistenciales, Ministry of Health, Chile, and Mutual de Seguridad de la Cámara Chilena de la Construcción.

Dynamic IgG seropositivity after rollout of CoronaVac and BNT162b2 COVID-19 vaccines in Chile: a sentinel surveillance study.

BACKGROUND: By July 14, 2021, 81·3 % of adults (aged ≥18 years) in Chile had received a first SARS-CoV-2 vaccine and 72·3% had received a second SARS-CoV-2 vaccine, with the majority of people given Sinovac's inactivated CoronaVac vaccine (75·3% of vaccines dispensed) or Pfizer-BioNTech's mRNA BNT162b2 vaccine (20·9% of vaccines dispensed). Due to the absence of simultaneous real-world data for these vaccines, we aimed to compare SARS-CoV-2 IgG positivity between vaccines using a dynamic national monitoring strategy. METHODS: From March 12, 2021, 28 testing stations for SARS-CoV-2 IgG detection were installed in hotspots based on cellular-phone mobility tracking within the most populated cities in Chile. Individuals voluntarily approaching the testing stations were invited to do a lateral flow test by finger prick and respond to a questionnaire on sociodemographic characteristics, vaccination status (including type of vaccine if one was received), variables associated with SARS-CoV-2 exposure, and comorbidities. We compared the proportion of individuals testing positive for anti-SARS-CoV-2 IgG across sites by week since vaccination between recipients of CoronaVac and BNT162b2. Unvaccinated participants served as a control population and were matched to vaccinated individuals on the basis of date of presentation to the testing station, gender, and age group. Individuals were excluded from the analysis if they were younger than 18 years, had no declared gender, had an invalid IgG test result, had previously tested positive for SARS-CoV-2 infection on PCR, could not recall their vaccination status, or had been immunised against COVID-19 with vaccines other than CoronaVac or BNT162b2. Here, we report data collected up to July 2, 2021. FINDINGS: Of 64 813 individuals enrolled, 56 261 were included in the final analysis, of whom 33 533 (59·6%) had received at least one dose of the CoronaVac vaccine, 8947 (15·9%) had received at least one dose of the BNT162b2 vaccine, and 13 781 (24·5%) had not received a vaccine. SARS-CoV-2 IgG positivity during week 4 after the first dose of CoronaVac was 28·1% (95% CI 25·0-31·2; 220 of 783 individuals), reaching a peak of 77·4% (75·5-79·3; 1473 of 1902 individuals) during week 3 after the second dose. SARS-CoV-2 IgG positivity during week 4 after the first dose of the BNT162b2 vaccine was 79·4% (75·7-83·1; 367 of 462 individuals), increasing to 96·5% (94·9-98·1; 497 of 515 individuals) during week 3 after the second dose and remaining above 92% until the end of the study. For unvaccinated individuals, IgG seropositivity ranged from 6·0% (4·4-7·6; 49 of 810 individuals) to 18·7% (12·5-24·9; 28 of 150 individuals) during the 5 month period. Regression analyses showed that IgG seropositivity was significantly lower in men than women and in people with diabetes or chronic diseases for CoronaVac vaccine recipients (p<0·0001), and for individuals aged 60 years and older compared with people aged 18-39 years for both vaccines (p<0·0001), 3-16 weeks after the second dose. INTERPRETATION: IgG seropositivity was lower after CoronaVac than after BNT162b2 and declined over time since vaccination for CoronaVac recipients but not BNT162b2 recipients. Prolonged IgG monitoring will allow further evaluation of seropositivity overtime, providing data, in conjunction with effectiveness studies, for possible future re-assessment of vaccination strategies. FUNDING: Instituto Sistemas Complejos de Ingeniería and Ministerio de Salud Chile. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

The effect of correlation and false negatives in pool testing strategies for COVID-19.

During the current COVID-19 pandemic, active testing has risen as a key component of many response strategies around the globe. Such strategies have a common denominator: the limited availability of diagnostic tests. In this context, pool testing strategies have emerged as a means to increase testing capacity. The efficiency gains obtained by using pool testing, derived from testing combined samples simultaneously, vary according to the spread of the SARS-CoV-2 virus in the population being tested. Motivated by the need for testing closed populations, such as long-term care facilities (LTCFs), where significant correlation in infections is expected, we develop a probabilistic model for settings where the test results are correlated, which we use to compute optimal pool sizes in the context of two-stage pool testing schemes. The proposed model incorporates the specificity and sensitivity of the test, which makes it possible to study the impact of these measures on both the expected number of tests required for diagnosing a population and the expected number and variance of false negatives. We use our experience implementing pool testing in LTCFs managed by SENAMA (Chile's National Service for the Elderly) to develop a simulation model of contagion dynamics inside LTCFs, which incorporates testing and quarantine policies implemented by SENAMA. We use this simulation to estimate the correlation of test results among collected samples when following SENAMA's testing guidelines. Our results show that correlation estimates are high in settings representative of LTCFs, which validates the use of the proposed model for incorporating correlation in determining optimal pool sizes for pool testing strategies. Generally, our results show that settings in which pool testing achieves efficiency gains, relative to individual testing, are likely to be found in practice. Moreover, the results show that incorporating correlation in the analysis of pool testing strategies both improves the expected efficiency and broadens the settings in which the technique is preferred over individual testing.

HIV Treatment in Resource-Limited Environments: Treatment Coverage and Insights.

BACKGROUND: The effects of antiretroviral treatment on the HIV epidemic are complex. HIV-infected individuals survive longer with treatment, but are less likely to transmit the disease. The standard coverage measure improves with the deaths of untreated individuals and does not consider the fact that some individuals may acquire the disease and die before receiving treatment, making it susceptible to overestimating the long-run performance of antiretroviral treatment programs. OBJECTIVE: The objective was to propose an alternative coverage definition to better measure the long-run performance of HIV treatment programs. METHODS: We introduced cumulative incidence-based coverage as an alternative to measure an HIV treatment program's success. To numerically compare the definitions, we extended a simulation model of HIV disease and treatment to represent a dynamic population that includes uninfected and HIV-infected individuals. Also, we estimated the additional resources required to implement various treatment policies in a resource-limited setting. RESULTS: In a synthetic population of 600,000 people of which 44,000 (7.6%) are infected, and eligible for treatment with a CD4 count of less than 500 cells/mm(3), assuming a World Health Organization (WHO)-defined coverage rate of 50% of eligible people, and treating these individuals with a single treatment regimen, the gap between the current WHO coverage definition and our proposed one is as much as 16% over a 10-year planning horizon. CONCLUSIONS: Cumulative incidence-based definition of coverage yields a more accurate representation of the long-run treatment success and along with the WHO and other definitions of coverage provides a better understanding of the HIV treatment progress.

Should expectations about the rate of new antiretroviral drug development impact the timing of HIV treatment initiation and expectations about treatment benefits?

BACKGROUND: Many analyses of HIV treatment decisions assume a fixed formulary of HIV drugs. However, new drugs are approved nearly twice a year, and the rate of availability of new drugs may affect treatment decisions, particularly when to initiate antiretroviral therapy (ART). OBJECTIVES: To determine the impact of considering the availability of new drugs on the optimal initiation criteria for ART and outcomes in patients with HIV/AIDS. METHODS: We enhanced a previously described simulation model of the optimal time to initiate ART to incorporate the rate of availability of new antiviral drugs. We assumed that the future rate of availability of new drugs would be similar to the past rate of availability of new drugs, and we estimated the past rate by fitting a statistical model to actual HIV drug approval data from 1982-2010. We then tested whether or not the future availability of new drugs affected the model-predicted optimal time to initiate ART based on clinical outcomes, considering treatment initiation thresholds of 200, 350, and 500 cells/mm3. We also quantified the impact of the future availability of new drugs on life expectancy (LE) and quality-adjusted life expectancy (QALE). RESULTS: In base case analysis, considering the availability of new drugs raised the optimal starting CD4 threshold for most patients to 500 cells/mm3. The predicted gains in outcomes due to availability of pipeline drugs were generally small (less than 1%), but for young patients with a high viral load could add as much as a 4.9% (1.73 years) increase in LE and a 8% (2.43 QALY) increase in QALE, because these patients were particularly likely to exhaust currently available ART regimens before they died. In sensitivity analysis, increasing the rate of availability of new drugs did not substantially alter the results. Lowering the toxicity of future ART drugs had greater potential to increase benefit for many patient groups, increasing QALE by as much as 10%. CONCLUSIONS: The future availability of new ART drugs without lower toxicity raises optimal treatment initiation for most patients, and improves clinical outcomes, especially for younger patients with higher viral loads. Reductions in toxicity of future ART drugs could impact optimal treatment initiation and improve clinical outcomes for all HIV patients.