Abstracts

Background

The COVID-19 pandemic has had a substantial impact on public health systems worldwide. Without an effective treatment and vaccine against SARS-CoV-2, various individual and community measures have been taken to minimize serious illness and deaths while containing the spread of the virus ¹1. Ayouni I, Maatoug J, Dhouib W, Zammit N, Fredj SB, Ghammam R, et al. Effective public health measures to mitigate the spread of COVID-19: a systematic review. BMC Public Health 2021; 21:1015..

Vaccines were a turning point for the pandemic. With accelerated trials, the first COVID-19 vaccine efficacy results were delivered less than a year after the first publication of the viral genome sequencing ²2. Duerr R, Dimartino D, Marier C, Zappile P, Wang G, Lighter J, et al. Dominance of Alpha and Iota variants in SARS-CoV-2 vaccine breakthrough infections in New York City. J Clin Investig 2021; 131:e152702.^,33. Zhu D, Dejnirattisai W, Supasa P, Liu C, Mentzer AJ, Ginn HM, et al. Evidence of escape of SARS-CoV-2 variant B.1.351 from natural and vaccine-induced sera. Cell 2021; 189:2348-61.. In Brazil, vaccination campaigns against COVID-19 began on January 17, 2021, with a phased program prioritizing age groups, health professionals, institutionalized people, and indigenous populations ⁴4. Valiati NCM, Villela DAM. Modelling policy combinations of vaccination and transmission suppression of SARS-CoV-2 in Rio de Janeiro, Brazil. Infect Dis Model 2022; 7:231-42.. Brazil ranks fourth globally in the absolute number of people fully vaccinated against COVID-19 ⁵5. Johns Hopkins University & Medicine. Vaccination progress across the world. https://coronavirus.jhu.edu/vaccines/international (accessed on 14/Feb/2022).
https://coronavirus.jhu.edu/vaccines/int... , with 85.8% of the population being fully vaccinated ⁶6. Ministério da Saúde. Programa Nacional de Imunizações - PNI. https://www.gov.br/saude/pt-br/coronavirus/vacinas/plano-nacional-de-operacionalizacao-da-vacina-contra-a-covid-19 (accessed on 06/Mar/2022).
https://www.gov.br/saude/pt-br/coronavir... . After implementing this measure, severe illnesses and deaths have been continuously declining, despite not following a linear pathway ⁷7. Ministério da Saúde. Painel Coronavírus. https://covid.saude.gov.br/ (accessed on 02/Apr/2022).
https://covid.saude.gov.br/... . Indeed, the longer it takes to contain the virus, the longer new viral variants have time to emerge and spread, which could lead to a resurgence of cases.

Recent studies highlighted that Brazilian vaccination campaigns played a relevant role in reducing the incidence of COVID-19 among health professionals ⁸8. Toniasso SCC, Fernandes FS, Joveleviths D, Dantas FF, Takahashi AY, Baldin CP, et al. Reduction in COVID-19 prevalence in healthcare workers in a university hospital in southern Brazil after the start of vaccination. Int J Infect Dis 2021; 109:283-5.^,99. Hitchings MDT, Ranzani OT, Torres MSS, Oliveira SB, Almiron M, Said R. Effectiveness of CoronaVac in the setting of high SARS-CoV-2P.1 variant transmission in Brazil: a test-negative case-control study. medRxiv 2021; 24 Jun. https://www.medrxiv.org/content/10.1101/2021.04.07.21255081v4. and in severe cases and deaths among older adults ¹⁰10. Victora CG, Castro MC, Gurzenda S, Medeiros AC, França GVA, Barros AJD. Estimating the early impact of vaccination against COVID-19 on deaths among elderly people in Brazil: analyses of routinely-collected data on vaccine coverage and mortality. EClinicalMedicine 2021; 38:101036.^,1111. Alencar CH, Cavalcanti LPG, Almeida MM, Barbosa PPL, Cavalcante KKS, Melo DN, et al. High effectiveness of SARS-CoV-2 vaccines in reducing COVID-19-related deaths in over 75-year-olds, Ceara´ State, Brazil. Trop Med Infect 2021; 6:129.^,1212. Ranzani OT, Hitchings MDT, Dorion M, D'Agostini TL, de Paula RC, de Paula OFP, et al. Effectiveness of the CoronaVac vaccine in older adults during a gamma variant associated epidemic of COVID-19 in Brazil: test negative case-control study. BMJ 2021; 374:n2015.. More recently, a study also demonstrated that vaccination for COVID-19 was significantly associated with reduced case fatality rates (CFRs) across all age groups in a municipality in Southern Brazil ¹³13. Passarelli-Araujo H, Pott-Junior H, Susuki AM, Olak AS, Pescim RR, Tomimatsu MFAI, et al. The impact of COVID-19 vaccination on case fatality rates in a city in Southern Brazil. Am J Infect Control 2022; 50:491-6.. Although vaccinated individuals may still get infected, they develop milder symptoms and have a lower death risk than unvaccinated subjects ¹⁴14. Mohammed I, Nauman A, Paul P, Ganesan S, Chen KH, Jalil SMS, et al. The efficacy and effectiveness of the COVID-19 vaccines in reducing infection, severity, hospitalization, and mortality: a systematic review. Hum Vaccin Immunother 2022; 18:2027160.. Thus, vaccination has empirically shown its effectiveness.

The success of vaccination depends on numerous factors, including efficacy and safety, availability, and public acceptance and compliance. To this end, few studies in Brazil have shown that vaccine hesitancy is directly related to efficacy and potential adverse side effects ¹⁵15. Moore DCBC, Nehab MF, Camacho KG, Reis AT, Junqueira-Marinho MF, Abramov DM, et al. Low COVID-19 vaccine hesitancy in Brazil. Vaccine 2021; 39:6262-8.^,1616. Ticona JPA, Nery Jr. N, Fofana MO, Ribeiro GS, Giorgi E, Reis MG, et al. Willingness to get the COVID-19 vaccine among residents of slum settlements. Vaccines (Basel) 2021; 9:951.. Thus, further local studies showing vaccine efficacy in reducing fatality rates may decrease the population’s vaccine hesitancy. This improved knowledge will allow the ongoing reassessment of public health interventions and policies based on local characteristics, maximizing their effectiveness.

CFR is an essential index that helps to understand the epidemiological characteristics of the COVID-19 outbreak ¹⁷17. Alimohamadi Y, Tola HH, Abbasi-Ghahramanloo A, Janani M, Sepandi M. Case fatality rate of COVID-19: a systematic review and meta-analysis. J Prev Med Hyg 2021; 62:E311-20.. It is defined as the ratio between the number of confirmed deaths from a disease and the number of reported cases in a given time. Certain points require caution and awareness when investigating the impact of COVID-19 vaccines on CFR. It is highly recognized that CFR is a metric sensitive to demographic factors (age-structure of diagnosed infection cases and age-specific fatality rates), delays in reported cases, and testing policies ¹⁸18. Dudel C, Riffe T, Acosta E, van Raalte A, Strozza C, Myrskylä M. Monitoring trends and differences in COVID-19 case-fatality rates using decomposition methods: contributions of age structure and age-specific fatality. PLoS One 2020; 15:e0238904.^,1919. Harman K, Allen H, Kall M, Dabrera G. Interpretation of COVID-19 case fatality risk measures in England. J Epidemiol Community Health 2021; 75:415-6.^,2020. Cao Y, Hiyoshi A, Montgomery S. COVID-19 case-fatality rate and demographic and socioeconomic influencers: worldwide spatial regression analysis based on country-level data. BMJ Open 2020; 10:e043560.. Another study also showed that the CFR depends not only on the effectiveness of vaccines in reducing deaths among the vaccinated but also on detecting infections among both vaccinated and unvaccinated individuals ²¹21. di Lego V, Sánchez-Romero M, Prskawetz A. The impact of COVID-19 vaccines on the case fatality rate: the importance of monitoring breakthrough infections. Int J Infect Dis 2022; 119:178-83.. If the same testing strategy is maintained before and after the beginning of vaccination campaigns, a decline in CFR may indicate that vaccines are preventing deaths ²¹21. di Lego V, Sánchez-Romero M, Prskawetz A. The impact of COVID-19 vaccines on the case fatality rate: the importance of monitoring breakthrough infections. Int J Infect Dis 2022; 119:178-83..

In this study, we contrast the behavior of the CFR between vaccinated and unvaccinated individuals in a municipality in Southern Brazil to understand the role of COVID-19 vaccination as a vital public health measure to prevent COVID-related deaths. We also discuss the primary public health interventions adopted by the municipal authorities to minimize the spread of the disease in the municipality. The underlying hypothesis from our work is that vaccinated individuals have lower fatality rates than those unvaccinated in all age groups. This study contributes to the discussion on how local policymakers should accurately measure vaccine effectiveness in reducing fatalities, considering the influence of demographic factors on these values to develop appropriate strategies for the ongoing reassessment of local public health interventions.

Methods

Study design and setting

This is an ecological study conducted in Arapongas, located in the north of the state of Paraná (Figure 1), with an estimated population of 126,545 inhabitants in 2021 ²²22. Instituto Brasileiro de Geografia e Estatística. Cidades e estados. Arapongas. https://www.ibge.gov.br/cidades-e-estados/pr/arapongas.html (accessed on 29/Dec/2021).
https://www.ibge.gov.br/cidades-e-estado... . Arapongas has a 382,215km² and population density of 272.49 inhabitants/km². Arapongas belongs to the 16th Health District among the 22 districts from Paraná; these are territorial divisions of political-administrative nature to make health actions more agile and efficient.

Participants

This study included all individuals within the Arapongas Municipal Health Department database with a confirmed COVID-19 diagnosis. The time interval considered comprises cases and deaths after the start of vaccination, on January 20, 2021, until December 31, 2021. A total of 16,437 confirmed cases and 425 deaths were reported during this period. The COVID-19 case definition followed the World Health Organization (WHO) criteria: an individual with a positive Nucleic Acid Amplification Test (NAAT) or a positive SARS-CoV-2 antigen rapid diagnostic test and meeting the probable or suspect case definition criteria ²³23. World Health Organization. WHO COVID-19 case definition. https://www.who.int/publications/i/item/WHO-2019-nCoV-Surveillance_Case_Definition-2022.1 (accessed on 27/Jan/2022).
https://www.who.int/publications/i/item/... .

The study was approved by the Research Ethics Committee of the State University of Londrina (reference n. 44128621.3.0000.5231).

Variables

Sociodemographic variables included age (years), sex (male, female), and vaccination status. Confirmed cases and deaths were grouped into unvaccinated, partially vaccinated, and fully vaccinated according to the vaccination status reported at the time of the COVID-19 notification. Complete vaccination status encompassed all individuals with ≥ 14 days after the second dose (for 2-dose vaccines) or a single dose (for the Janssen vaccine). Incompletely vaccinated were defined as those individuals who received only one dose (in the case of 2-dose vaccines) or were less than 14 days after the second dose or after a single-dose vaccine (Janssen).

Case fatality rates definition

The CFR measures the proportion of individuals with a specific condition who died from that condition during the reference period; it is therefore a measure of severity among detected cases ²⁴24. World Health Organization. Estimating mortality from COVID-19. https://www.who.int/publications/i/item/WHO-2019-nCoV-Sci-Brief-Mortality-2020.1 (accessed on 14/Jan/2022).
https://www.who.int/publications/i/item/... . In this article, CFR metric refers to the ratio of COVID-19 deaths (D) divided by the number of confirmed cases (N): CFR = D/N.

Statistical analysis

CFRs were calculated according to the vaccination status to compare immunization effectiveness. Since CFR is a crude rate, differences in age distributions of confirmed cases among subgroups with different vaccination statuses may strongly affect the results ¹³13. Passarelli-Araujo H, Pott-Junior H, Susuki AM, Olak AS, Pescim RR, Tomimatsu MFAI, et al. The impact of COVID-19 vaccination on case fatality rates in a city in Southern Brazil. Am J Infect Control 2022; 50:491-6.. To make reliable comparisons between CFRs, the average age distribution of confirmed cases among the vaccination statuses was adopted as a standard age distribution. The age-standardized CFR is given by:

where C _i represents the age-specific CFRs and P _i is the proportion of cases in each age group among the vaccination statuses.

To compare the proportions of cases and deaths among groups (unvaccinated, partially, and fully vaccinated subjects), pairwise comparisons between pairs of proportions (Z-tests) with correction for multiple testing were performed.

All analyses were conducted in R software program (http://www.r-project.org).

Results

Figure 2 shows the leading public health measures at municipal and state levels through decrees and other actions adopted to minimize the spread of the disease between 2020 and 2021. The numbers of confirmed cases and deaths were made available periodically, and the Arapongas Municipal Health Department maintained a close dialogue with researchers from higher education institutions with high regional impact, such as the State University of Londrina. Moreover, local guidelines were made available to the Arapongas population as part of the strategy to combat the disease.

In 2021, COVID-19 vaccination campaigns began in the municipality, following the Brazilian National Immunization Program, which established priority groups to be vaccinated. Vaccination was conducted in a phased schedule according to the guidelines established by the Brazilian Ministry of Health. Up to December 31, 2021, 23,551 and 575 confirmed cases and deaths had occurred in Arapongas, respectively (Figure 2).

Figure 3 shows the distribution of COVID-19 cases and deaths stratified by age, sex, and vaccination status. We observed significant differences in age compositions among vaccination statuses. The fully vaccinated population had a greater number of older adults, contrasting with unvaccinated and partially vaccinated groups. The unvaccinated group had the highest proportion of individuals aged under 60 years for both sexes, resulting in a younger age composition than that observed among the other groups. In the fully vaccinated subgroup, deaths occurred only among older adults (60+ years), while in the unvaccinated subgroup, deaths predominated in the 20-59 age group but occurred in all age ranges. Deaths occurred more frequently in men than in women, while the frequency of confirmed cases was more proportional between the sexes (Figure 3).

Table 1 depicts confirmed cases of COVID-19, deaths, and CFRs (per 100) according to vaccination status and age. The overall CFR of the studied population was 2.59. When considering the age-standardized CFR, a complete vaccination status had the lowest value; the measure for complete vaccination status (CFR = 2.42%) is about twice as low as the CFR of unvaccinated and incomplete vaccination statuses (4.55%). Individuals with complete vaccination also showed lower age-specific CFRs in all age groups above 60 years than unvaccinated populations (Table 1). Figure 4 shows (a) unadjusted CFR; (b) age-standardized CFR; and (c) CFR in each age range, showing that these rates are always lower in the vaccinated population in groups (b) and (c), reinforcing the importance of age adjustments.

According to vaccination status, the proportions of cases and deaths are followed by letters in Table 1. The same letters for the same age group indicate no significant differences among groups, while different letters indicate statistically significant differences (Table 1).

Discussion

This study evaluated the behavior of CFRs among vaccinated and unvaccinated individuals in a municipality in Southern Brazil to understand the role of COVID-19 vaccination as a vital public health measure in preventing COVID-related deaths. Our results showed that age composition directly impacts the analysis of CFRs among subgroups of vaccination status. We also showed that complete vaccination is associated with lower COVID-19 fatality rates than the other vaccination status, regardless of age.

Through January/2021, Arapongas had a higher number of deaths (472.7/100,000 inhabitants) compared with other municipalities in Paraná State, such as Londrina (408.9/100,000 inhabitants) and Curitiba (405.6/100,000 inhabitants). Notably, Arapongas followed state and national guidelines and contingency plans to mitigate community transmission of SARS-CoV-2 (Figure 2). Brazilian Unified National Health System (SUS) is decentralized, and local governments have the autonomy to implement their laws and public health interventions ¹⁶16. Ticona JPA, Nery Jr. N, Fofana MO, Ribeiro GS, Giorgi E, Reis MG, et al. Willingness to get the COVID-19 vaccine among residents of slum settlements. Vaccines (Basel) 2021; 9:951.. Thus, a series of measures were taken by the Arapongas Municipal Health Department to reduce community transmission of SARS-CoV-2 (Figure 2).

However, the outcomes of individual and community-based measures are difficult to measure as they depend on different scenarios. Even so, a recent study conducted in Rio de Janeiro, Brazil, showed that the combination of vaccination and non-pharmaceutical public health measures potentially reduced the number of hospitalizations by 380+ and 66+ thousand cases, respectively, compared with an alternative scenario with the absence of such policies ⁴4. Valiati NCM, Villela DAM. Modelling policy combinations of vaccination and transmission suppression of SARS-CoV-2 in Rio de Janeiro, Brazil. Infect Dis Model 2022; 7:231-42.. Notably, the existing socioeconomic inequalities in Brazil may have also contributed to the course of the epidemic, affecting the adherence to individual- and community-based measures ²⁵25. Rocha R, Atun R, Massuda A, Rache B, Spinola P, Nunes L, et al. Effect of socioeconomic inequalities and vulnerabilities on health-system preparedness and response to COVID-19 in Brazil: a comprehensive analysis. Lancet Glob Health 2021; 9:e782-92. and, potentially explaining the high number of cases nationally. Considering that health information plays a fundamental role in the adherence of the local population to individual- and community-based measures the Arapongas Municipal Health Department published epidemiological bulletins on the local sanitary situation throughout the pandemic, soughing to periodically inform the population and the local press about the situation in the municipality during the pandemic.

The arrival of vaccines was a turning point for the city. Here, we demonstrated that a full vaccination status, especially among older adults, was associated with the lowest age-specific fatality rates compared with unvaccinated and partially vaccinated groups. This finding strengthens the role of vaccination as a critical measure for preventing deaths among infected people and aligns with previous findings from other studies. Liang et al. ²⁶26. Liang LL, Kuo HS, Ho HJ, Wu CY. COVID-19 vaccinations are associated with reduced fatality rates: evidence from cross-county quasi-experiments. J Glob Health 2021; 11:05019. evaluated the association between COVID-19 vaccine coverage with CFR on a global scale. The authors showed that a 10% increase in vaccine coverage was associated with a 7.6% reduction in the CFR (95%CI: -12.6; -2.7, p = 0.002) ²⁶26. Liang LL, Kuo HS, Ho HJ, Wu CY. COVID-19 vaccinations are associated with reduced fatality rates: evidence from cross-county quasi-experiments. J Glob Health 2021; 11:05019.. Indeed, this association was stronger in countries with more effective governments - defined by the authors as those with an intrinsic ability or preparedness to implement COVID-19 immunization programs and high-quality public services (-8.3%; 95%CI: -13.6; -3.1, p = 0.002). Another study showed that COVID-19 vaccination was significantly associated with reduced CFRs in all age groups in Londrina ¹³. The authors also argued that age composition is a potential explanation for differences in overall CFRs among vaccinated and unvaccinated populations.

The role of age composition cannot be neglected when investigating disparities in fatality rates across populations and this factor has also been reinforced in other studies ¹⁸18. Dudel C, Riffe T, Acosta E, van Raalte A, Strozza C, Myrskylä M. Monitoring trends and differences in COVID-19 case-fatality rates using decomposition methods: contributions of age structure and age-specific fatality. PLoS One 2020; 15:e0238904.^,2727. Dowd JB, Andriano L, Brazel DM, Rotondi V, Block P, Ding X, et al. Demographic science aids in understanding the spread and fatality rates of COVID-19. Proc Natl Acad Sci U S A 2020; 117:9696-8.. For example, in Arapongas, there were more older adults among those with complete vaccination than in the remaining two groups. As COVID-19-related mortality increases with age ²⁸28. O'Driscoll M, Ribeiro Dos Santos G, Wang L, Cummings DAT, Azman AS, Paireau J, et al. Age-specific mortality and immunity patterns of SARS-CoV-2. Nature 2021; 590:140-5., it is expected that the CFR will be higher among the group with a higher proportion of older adults precisely because the CFR is a crude indicator and is highly sensitive to the age composition of the population ¹⁸18. Dudel C, Riffe T, Acosta E, van Raalte A, Strozza C, Myrskylä M. Monitoring trends and differences in COVID-19 case-fatality rates using decomposition methods: contributions of age structure and age-specific fatality. PLoS One 2020; 15:e0238904.. Thus, in a hypothetical scenario, the unadjusted CFR was expected to be higher among the individuals with complete vaccination status, even if the age-specific risk of death was the same. For this reason, considering the effects that the population’s age composition has on this measure is essential to avoid misinterpretation of the impact of vaccination on CFRs.

Moreover, there are several reasons for the higher COVID-19 mortality among older adults ²⁹29. Pott Junior H, Cominetti MR. Comorbidities predict 30-day hospital mortality of older adults with COVID-19. Geriatr Nurs 2021; 42:1024-8.. Notably, the observed higher fatality rates among vaccinated older adults may be associated with a reduced response to vaccination. Several studies have shown that most non-COVID-19 vaccines currently used are less immunogenic and effective in older adults than younger adults ³⁰30. Ciabattini A, Nardini C, Santoro F, Garagnani P, Franceschi C, Medaglini D. Vaccination in the elderly: the challenge of immune changes with aging. Semin Immunol 2018; 40:83-94.. COVID-19 vaccines followed the same pattern. This evidence suggests that older adults need to be closely monitored and require additional vaccine doses to ensure stronger, long-lasting immunization ³¹31. Muller L, Andrée M, Moskorz W, Drexler I, Walotka L, Grothmann R, et al. Age-dependent immune response to the Biontech/Pfizer BNT162b2 coronavirus disease 2019 vaccination. Clin Infect Dis 2021; 73:2065-72..

Although our study is inherently essential since it contributes to the literature by evaluating the impact of vaccination on case fatality rates in a Brazilian municipality, we acknowledge the existence of some methodological limitations. First, the low number of cases and deaths in some age categories precluded us from employing other statistics to estimate CFRs for all age groups by vaccination status. Second, the CFR might be underestimated due to the time-lag bias associated with COVID-19 case diagnosis and reports in the municipality. Individuals who test are usually those most concerned about individual and collective health or belong to a specific segment of the general population, such as transport and health workers, for example. Also, asymptomatic cases of COVID-19, patients with mild symptoms, or individuals who are misdiagnosed could be left out of the denominator ³²32. Rajgor DD, Lee MH, Archuleta S, Bagdasarian N, Quek SC. The many estimates of the COVID-19 case fatality rate. Lancet Infect Dis 2020; 20:776-7.. The underreporting of cases could lead to an inaccurate CFR estimation ³³33. Alimohamadi Y, Tola HH, Abbasi-Ghahramanloo A, Janani M, Sepandi M. Case fatality rate of COVID-19: a systematic review and meta-analysis. J Prev Med Hyg 2021; 62:E311-20.. Although these factors are potential reporting biases in the study, we do not expect them to significantly impact the results or change the overall conclusions of the work. The last limitation refers to the impossibility of assessing other individuals’ characteristics such as comorbidities and socioeconomic status by the database and incorporating them into the analysis due to the absence of such information. Despite these limitations, the evidence from this study is vital to the ongoing reassessment of public health interventions and policies.

Conclusions

The age composition of COVID-19 cases significantly affects group-wise estimates of case fatality rates. This evidence points to the need to standardize CFR by age before analyzing differences between groups. Nevertheless, individuals with a full vaccination status experience lower fatality rates than those with another vaccination status. This improved knowledge is beneficial for the continuous reassessment of public health interventions and policies in the fight against COVID-19 spread.

Acknowledgments

We acknowledge the Brazilian Coordination for the Improvement of Higher Education Personnel (CAPES) for the financial support (scholarship); the Arapongas Municipal Health Department for providing the data; and the Interdisciplinary Center for Public Management (NIGEP), State University of Londrina, coordinated by Prof. Vera Suguihiro and Prof. Saulo F. A. Vieira.

References

Publication Dates

History