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The Journal of Allergy and Clinical Immunology: Global logoLink to The Journal of Allergy and Clinical Immunology: Global
. 2023 Feb 21;2(2):100083. doi: 10.1016/j.jacig.2023.100083

Robust specific RBD responses and neutralizing antibodies after ChAdOx1 nCoV-19 and CoronaVac vaccination in SARS-CoV-2– seropositive individuals

Edgar Ruz Fernandes a, Monica Taminato b, Juliana de Souza Apostolico a, Maria Cristina Gabrielonni b, Victoria Alves Santos Lunardelli a, Juliana Terzi Maricato a, Monica Levy Andersen c,d, Sergio Tufik c,d, Daniela Santoro Rosa a,∗
PMCID: PMC9942448  PMID: 36845213

Abstract

Background

The pandemic unleashed by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 500 million people worldwide and caused more than 6 million deaths. Cellular and humoral immunity induced by infection or immunization are key factors in controlling the viral burden and avoiding the recurrence of coronavirus disease. The duration and effectiveness of immunity after infection is relevant to pandemic policy interventions, including the timing of vaccine boosters.

Objectives

We sought to evaluate longitudinal binding and functional antibodies against SARS-CoV-2 receptor-binding domain in police officers and health care workers with a history of coronavirus disease 2019 and compare with SARS-CoV-2–naive individuals after vaccination with adenovirus-based ChAdOx1 nCoV-19 (AstraZeneca-Fiocruz) or the inactivated CoronaVac vaccine (Sinovac-Butantan Institute).

Methods

A total of 208 participants were vaccinated. Of these, 126 (60.57%) received the ChAdOx1 nCoV-19 vaccine and 82 (39.42%) received the CoronaVac vaccine. Prevaccination and postvaccination blood was collected, and the amount of anti–SARS-CoV-2 IgG and the neutralizing ability of the antibodies to block the interaction between angiotensin-converting enzyme 2 and receptor-binding domain were determined.

Results

Subjects with preexisting SARS-CoV-2 immunity and who received a single dose of ChAdOx1 nCoV-19 or CoronaVac have similar or superior antibody levels when compared with levels in seronegative individuals even after 2 doses of the vaccine. Neutralizing antibody titers of seropositive individuals were higher with a single dose of either ChAdOx1 nCoV-19 or CoronaVac compared with those of seronegative individuals. After 2 doses, both groups reached a plateau response.

Conclusions

Our data reinforce the importance of vaccine boosters to increase specific binding and neutralizing SARS-CoV-2 antibodies.

Key words: SARS-CoV-2, COVID-19, CoronaVac, ChAdOx1 nCoV-19, antibodies

In the last 2 years, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has challenged the health care system, as well as the science of vaccine development. The discovery and licensing of different vaccines against coronavirus disease 2019 (COVID-19) played a major role in controlling the number of related severe diseases and deaths.1 The most frequently administrated vaccines for the first 2-dose regimen in Brazil were the inactivated CoronaVac (Sinovac Biotech)2,3 and the adenovirus vectored ChAdOx1 nCoV-19 (Vaxzevria/Fiocruz).4,5 However, the effectiveness of these vaccines wanes over time,1,5, 6, 7, 8 which led the Brazilian COVID-19 vaccination program to include the BNT162b2 (Pfizer-BioNTech) preferentially as a booster dose after completing primary vaccination.9 Several studies have investigated humoral and cellular immune responses after CoronaVac2,10 and ChAdOx1 nCoV-19 vaccination in different clinical cohorts.4,11,12 From such studies, a relationship between anti–SARS-CoV-2 antibodies and vaccine effectiveness became evident, as well as the neutralizing antibodies–dependent protection.6,13 The vast majority of neutralizing antibodies produced after immunization target the SARS-CoV-2 receptor-binding domain (RBD) of the Spike protein.14,15 The impact of preexisting immunity on vaccine-induced antibody response was mainly studied with mRNA-based vaccines including BNT162b2 and mRNA-1273.16, 17, 18

Some of the vaccines available to date include mRNA-based vaccines encoding RBD, and the effect of preexisting immunity on vaccine-induced antibody responses has been investigated primarily using BNT162b2 and RNA-1273.16, 17, 18 Nonetheless, the impact of preexisting humoral responses against RBD in CoronaVac and ChAdOx1 nCoV-19 vaccination settings remains poorly explored.

Here, we evaluated binding and functional antibodies against RBD in individuals (police officers and health care workers) with a history of COVID-19 and compared with SARS-CoV-2–naive individuals after vaccination with ChAdOx1 nCoV-19 and CoronaVac. We detected subtle/relevant differences among the vaccinees who presented previous SARS-CoV-2 infection. We observed that the antibody response to the first vaccine dose in individuals with preexisting immunity was similar to or exceeded (for the ChAdOx1 nCoV-19 group) the titers found in seronegative individuals after the second dose. Furthermore, no enhancement in antibody response after the second dose was detected in SARS-CoV-2–experienced individuals for both ChAdOx1 nCoV-19 and CoronaVac vaccines. However, after completing the immunization regimen, seropositive participants with previous exposure to SARS-CoV-2 presented higher or similar antibody responses than the seronegative. By functional assay, after 1 dose, the neutralizing ability in individuals with preexisting immunity was similar to or slightly exceeded the neutralization capacity in naive individuals after the second dose. When the immunization regimen was completed, vaccine recipients had similar neutralization ability despite the initial serostatus.

Methods

Study design and participants

Healthy adult police officers and health care workers aged 18 to 70 years receiving routine COVID-19 vaccinations were invited to participate. Eligible participants were healthy at the time of vaccination/sample collection and provided written informed consent. The exclusion criteria included the chronic use of immunosuppressant medication, oral corticosteroids, as well as any other condition that might lead to immune impairment. The presence of any clinical manifestation compatible with COVID-19, including temperature of at least 38°C within the 24 hours before the planned vaccine dose, was also considered an exclusion criteria. The use of antipyretic medication before and after vaccination was recorded. The study protocol was reviewed and approved by the Federal University of São Paulo Ethics Committee (Certificado de Apresentação de Apreciação Ética [CAAE] no. 45208321.9.0000.5505, CEP project no. 0355/2021). Participating donors received 2 doses of the adenovirus-based ChAdOx1 nCoV-19 (AstraZeneca-Fiocruz) or the inactivated CoronaVac vaccine (Sinovac-Butantan Institute) in a 12- or 4-week interval, respectively. A total of 208 participants were vaccinated. Of these, 126 (60.57%) received the ChAdOx1 nCoV-19 vaccine and 82 (39.42%) received the CoronaVac vaccine. Prevaccination and postvaccination blood was collected, and all participants answered a survey about local (eg, pain and swelling) as well as systemic side effects (eg, fever and headache). All samples were coded before processing, and all tests were performed blindly. History of SARS-CoV-2 infection was determined by either self-reported history of positive PCR test result and/or positive RBD antibody test result. Breakthrough infections were communicated.

SARS-CoV-2 IgG antibodies

The amount of anti–SARS-CoV-2 antibodies was evaluated using the commercial standard immunoassay SARS-CoV-2 IgG (Abbott, Chicago, Ill) according to the manufacturer’s protocol. The chemiluminescent immunoassay provided quantitative determination of IgG antibodies against the spike RBD (SARS-CoV-2 IgG II Quant, Abbott). The results were provided in arbitrary units (AU) per milliliter, as defined by the manufacturer and ranging between 6.8 and 40.000 AU/mL for anti-RBD antibodies (a level of >50 AU/mL was considered positive).

Angiotensin-converting enzyme 2-RBD antibody–blocking assay

The neutralizing capacity was determined by the ability of the antibodies to block the interaction between angiotensin-converting enzyme 2 and RBD and was performed with the cPass Neutralization Antibody Detection Kit (GenScript, Piscataway, NJ), also known as the SARS-CoV-2 surrogate Virus Neutralization Test (sVNT) Kit according to the manufacturer’s instructions and as previously described.19 Neutralization rates above 30% were considered positive.

Statistical analysis

Statistical analysis was performed using GraphPad Prism software version 9.0. Group comparisons were performed using 2-way ANOVA followed by Tukey’s multiple comparison test. Spearman test was used to calculate correlation where indicated. P values less than .05 were considered statistically significant.

Results

Immunization with ChAdOx1 nCoV-19 and CoronaVac induces seroconversion

To determine whether a population previously infected or not with SARS-CoV-2 displays different antibody responses after vaccination, we vaccinated and screened 208 healthy adult police officers and health care workers in São Paulo, Brazil. Of these, 126 (60.57%) received the ChAdOx1 nCoV-19 vaccine and 82 (39.42%) received the CoronaVac vaccine (Table I).

Table I.

Population description and self-reported disease data

Cohort characteristics ChAdOx1 nCoV-19
 Coronavac
 Total
(N = 126; 60.57%) (N = 82; 39.42%) (N = 208)
Sex: female 45 (35) 54 (65) 102 (49)
Age (y, average) 41 35
COVID-19 positive before vaccine 40 (31.6) 12 (14.2) 52 (25)
COVID-19 positive first dose vaccine 3 (2.2) 2 (2.4) 5 (2.2)
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Values are n (%) unless otherwise indicated.

We actively analyzed all vaccinees for adverse events and observed a higher proportion of ChAdOx1 nCoV-19 vaccine-related adverse events (Table II). However, all identified events were expected. None of the vaccinated participants needed to be hospitalized or had a serious event. Fever and systemic events such as diarrhea and myalgia were predominant and more intensely reported after the first dose of ChAdOx1 nCoV-19.

Table II.

Distribution table of vaccine-related adverse events after the first and second doses

Self-reported events ChAdOx1 nCoV-19
 CoronaVac
First dose (N = 126) Second dose (N = 103) First dose (N = 82) Second dose (N = 74)
Adverse events 91(72.2) 29 (28) 13 (15.8) 3 (4.0)
Pain 23 (18.3) 3 (2.9) 11 (13.4) 1 (1.3)
Lump 7 (5.2) 5 (4.8) 0 (0) 0 (0)
Fever 74 (58.8) 9 (8.7) 5 (6.9) 1 (1.3)
Systemic events 81 (64.3) 28 (27) 7 (8.5) 1 (1.3)
Medical attention 12 (9) 1 (0.9) 0 (0) 0 (0)
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Values are n (%).

Of the 126 individuals who received the first ChAdOx1 nCoV-19 vaccine, 43.65% were considered seropositive based on the RBD-specific antibody titer before vaccination (Fig 1). After the first dose, the frequency of seropositive individuals increased to 91.26%, indicating either seroconversion or booster of previously acquired immunity. After the second dose, 3.17% of the individuals remained seronegative (Fig 1). However, CoronaVac elicited 89.33% and 100% of seroconversion after the prime and booster doses, respectively (Fig 2).

Fig 1.

Fig 1

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RBD-specific antibody response before and after vaccination with the ChAdOx1 nCoV-19 vaccine. One hundred twenty-six individuals received the ChAdOx1 nCoV-19 vaccine and tested for quantitative determination of IgG antibodies against the spike RBD (SARS-CoV-2 IgG II Quant, Abbott) by chemiluminescent immunoassay. The results are displayed in AU per milliliter, as defined by the manufacturer and ranging between 6.8 and 40,000 AU/mL for anti-RBD antibodies (a level of >50 AU/mL was considered positive).

Fig 2.

Fig 2

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RBD-specific antibody response before and after CoronaVac vaccination. A total of 82 individuals received the CoronaVac vaccine and tested for quantitative determination of IgG antibodies against the spike RBD (SARS-CoV-2 IgG II Quant, Abbott) by chemiluminescent immunoassay. The results are displayed in AU per milliliter, as defined by the manufacturer and ranging between 6.8 and 40,000 AU/mL for anti-RBD antibodies (a level of >50 AU/mL was considered positive).

Vaccination with ChAdOx1 nCoV-19 and CoronaVac booster previous infection acquired immunity

Next, we compared the antibody response elicited by vaccination in individuals who were previously seropositive and/or seronegative. Before vaccination with ChAdOx1 nCoV-19, seropositive individuals presented RBD-specific antibody response (average 816.33 AU/mL) that was 93.8-fold higher when compared with that of seronegative individuals (average 8.70 AU/mL) (Fig 3, A). In the ChAdOx1 nCoV-19–seropositive group, we observed an increase of 10.73- and 1.34-fold after the first dose and the second dose, respectively (Fig 3, A). In other words, we observed that the antibody response in seropositive individuals reached a plateau after the first dose and did not increase significantly after the booster. In contrast, a booster dose was essential to increase the antibody response in ChAdOx1 nCoV-19 seronegative group, with an increase relatively higher (74.02- and 3.47-fold, respectively). Finally, when we compared the magnitude of the antibody response in ChAdOx1 nCoV-19 seropositive and seronegative groups after 2 doses, we observed that previous infection with SARS-CoV-2 contributes to a 13.59- and 5.25-fold increase, respectively. In summary, we detected that the antibody response in individuals with preexisting immunity to SARS-CoV-2 was superior to that in the seronegative group even after the booster.

Fig 3.

Fig 3

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Vaccination with ChAdOx1 nCoV-19 and CoronaVac booster previously acquired immunity. A total of 208 participants were vaccinated. Of these, 126 received the ChAdOx1 nCoV-19 vaccine (A) and 82 received the CoronaVac vaccine (B). Prevaccination and postvaccination (12 weeks or 30 days after first; and 30 days after second dose) blood was collected and the amount of anti–SARS-CoV-2 RBD antibodies was assessed by chemiluminescent immunoassay using SARS-CoV-2 IgG II (Quant, Abbott) according to the manufacturer’s instructions. Sera from seronegative participants are represented by gray circles and seropositive by red squares for ChAdOx1 nCoV-19 vaccine (A) or blue squares for CoronaVac vaccine (B). ns, Nonsignificant. ∗∗∗P < .001; ∗∗∗∗P < .0001.

Before vaccination with CoronaVac, seropositive individuals presented 81.9-fold higher antibody levels (Fig 3, B) than seronegative individuals (average 643.26 AU/mL and 7.85 AU/mL, respectively). After vaccination, we observed an increase in SARS-CoV-2 specific IgG levels after the first dose and a slightly lower increase after the second dose (Fig 3, B). The CoronaVac-seropositive group presented an increase of 3.92- and 0.97-fold after the first dose and the second dose, respectively. For the seronegative group, a 22.92- and 8.12-fold increase, respectively, was observed. When we compared the responses of CoronaVac-seropositive and -seronegative groups after the 2-dose regimen, we found that preexisting SARS-CoV-2 antibodies contribute to a 14.02- and 1.67-fold increase, respectively. It is noteworthy that after the CoronaVac booster dose, the antibody response in individuals previously seronegative and seropositive was similar (Fig 3, B). The results confirm that previous SARS-CoV-2 infection favors the development of a faster and more robust IgG-specific production. Although we observed differences between the antibody levels after ChAdOx1 nCoV-19 and CoronaVac vaccination, the samples were collected at different time points after immunization, so this should not be taken solely as evidence that one vaccine is more efficacious than the other.

Vaccination induces highly neutralizing antibodies

For both vaccines, we observed that antibody response after the first dose was significantly lower in seronegative subjects than in individuals with preexisting immunity to SARS-CoV-2, confirming that natural infection potentially contributes to a higher humoral response. These results prompted us to analyze the neutralizing potential of the antibodies produced after vaccination in previously seronegative and seropositive individuals. Indeed, we found that before the first vaccine dose, the neutralizing ability of sera from seropositive individuals was considerably higher than that observed in seronegative subjects after the first dose of ChAdOx1 nCoV-19 (Fig 4, A) or CoronaVac (Fig 4, B). After the first dose, in both vaccine groups, seronegative individuals presented a lower neutralization ability compared with individuals who were previously seropositive (Fig 4, A and B). After the first dose, the neutralization capacity in individuals with preexisting immunity was similar (ChAdOx1 nCoV-19) or slightly exceeded (CoronaVac) the neutralization capacity in naive individuals after the second dose. After completing the 2-dose regimen, ChAdOx1 nCoV-19 or CoronaVac recipients presented similar neutralization ability despite the initial serostatus, reinforcing the importance of a vaccine booster to elicit a protective response.

Fig 4.

Fig 4

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Vaccination with ChAdOx1 nCoV-19 and CoronaVac induces highly neutralizing antibodies. Neutralizing antibodies in seronegative (gray circles) and seropositive individuals before and after the first and second doses of ChAdOx1 nCoV-19 (red squares; A) or CoronaVac vaccines (blue squares; B). ACE2, Angiotensin-converting enzyme 2; ns, nonsignificant. The neutralizing capacity was determined by the ability of the antibodies to block the ACE2-RBD interaction and was performed with cPass Neutralization Antibody Detection Kit (GenScript). ∗P < .05; ∗∗∗∗P < .0001.

Finally, our next question was whether the antibody concentration correlated with the neutralization capacity after vaccination. As expected, an increased concentration of antibodies was closely correlated with a higher neutralization capacity for either ChAdOx1 nCoV-19 (Fig 5, A) or CoronaVac (Fig 5, B) vaccine recipients. These results strengthen the importance of a vaccine booster to increase antibody titers and are essential to increase the neutralization capacity against SARS-CoV-2.

Fig 5.

Fig 5

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Correlation between the antibody response and neutralizing capacity. Antibody levels correlate with the percentage of neutralization after vaccination with (A) ChAdOx1 nCoV-19 or (B) CoronaVac. R2 and P values are depicted in each plot after Spearman correlation test.

Discussion

SARS-CoV-2 infection triggers an inflammatory immune response that initiates T- and B-cell adaptive responses. In most individuals, antibody production following immune activation helps to control the viral burden that mitigates the ongoing infection.20,21 The B-cell responses, which lead to the production of neutralizing antibodies, are of utmost importance for the control of most viral infections.22 Highly neutralizing antibodies are commonly found in most COVID-19 convalescent patients.23,24 However, it is important to evaluate the effect of preexisting immunity in vaccine-induced humoral responses. The Virus Neutralization Test method has been widely used and considered the criterion standard for evaluating neutralizing antibodies. Because of the need for BSL-3 environment to perform, alternative methods have been developed to make the test faster, easier, and more accessible. Among them, the main and most widely used currently is the sVNT. Recent work has shown an agreement of more than 95% between Virus Neutralization Test and sVNT, indicating that sVNT is a very reliable method for the determination of the neutralizing ability of anti–SARS-CoV-2 antibodies.25

Here, we demonstrate that previous exposure to SARS-CoV-2 primed RBD-specific antibody-producing cells that are boosted after a single dose with either ChAdOx1 nCoV-19 or CoronaVac, leading to superior neutralizing capacity. At the same time, at least 2 doses are necessary to match the neutralization profile of seronegative to seropositive individuals. A previous report demonstrated sustained humoral immunity in patients with asymptomatic COVID-19.26 In this sense, our results suggest that seroconversion must have been achieved because of an asymptomatic or mild infection. Most individuals infected with SARS-CoV-2 develop antibodies to the Spike and Nucleocapsid (N) proteins, which are used as antigens in serological tests.27,28 However, highly neutralizing antibodies are mostly specific for RBD. These antibodies play a crucial role in limiting viral replication in the host, which limits disease progression.29 Neutralizing antibody responses peak within 3 to 5 weeks after infection, and there is a higher proportion of IgG antibodies targeting RBD, compared with nucleocapsid, in outpatients with mild disease compared with critically ill patients.28 Estimation of the half-life of the neutralization titer in the first 70 days after infection suggests an initial half-life of approximately 55 days,30 whereas a long-term analysis suggested a general half-life of 90 days in the first 8 months after infection.31 In this sense, a good strategy to track antibody-associated protection is to investigate RBD-specific antibody production.

Vaccines against SARS-CoV-2 have greatly reduced the morbidity and mortality associated with infection and are considered the most promising approach for controlling the pandemic. Currently licensed vaccines have shown an efficacy of up to 95% in preventing laboratory-confirmed infection in the first few months after vaccination.32,33 Most vaccines against COVID-19 use, through different platforms, the Spike protein as an immunogen, which contains the RBD domain, because this is the main target of neutralizing antibodies.34 Among the vaccines that have already been officially approved for use in the population, we studied the humoral immune response of subjects vaccinated with ChAdOx1 nCoV-19 vaccine (replication-deficient simian adenovirus expressing full-length SARS-CoV-2)11 and CoronaVac vaccine (inactivated SARS-CoV-2).10 So far, ChAdOx1 vaccine is not recommended for use in the United States except in limited circumstances (inability to tolerate mRNA vaccines or Novavax, or refusal of all other vaccines), but in Brazil, ChAdOx1 together with CoronaVac was the most frequently administered vaccine.

As mentioned before, studies point to a strong relationship between high anti-Spike IgG titers and mild symptoms, as well as protection against severe cases.35 We observed a strong correlation between anti-RBD IgG response and neutralizing capacity in samples from individuals vaccinated with ChAdOx1 nCoV-19 and CoronaVac. Indeed, lower anti-RBD IgG antibody titers are correlated with an increased risk of SARS-CoV-2 infection in individuals vaccinated with mRNA-1273 (Moderna)36 and BNT162b2 (Pfizer)37 vaccines. Furthermore, lower anti-Spike antibody levels are correlated with increased mortality and viral spread in patients with severe COVID-19.38

Individuals vaccinated with ChAdOx1 nCoV-19 (Oxford/AstraZeneca) developed neutralizing IgG antibodies, mainly IgG1 and IgG3,4 28 days after immunization that increased after the second dose of immunization.11 Furthermore, immunized subjects developed specific T-cell responses 14 days after immunization.11 The CoronaVac inactivated virus vaccine (Sinovac Biotech) showed seroconversion after the second dose in 95% of patients and was also able to induce high titers of neutralizing antibodies2 after 2 doses administered.2 A recent study compared the response generated by different SARS-CoV-2 vaccines and observed that BNT162b2 induced the highest levels of anti-RBD IgG antibodies, followed by ChAdOx1 nCoV-19 and CoronaVac.39 Some studies have shown lower antibody titers after vaccination with ChAdOx1 nCoV-19 than after vaccination with BNT162b2. This may be related to the different time points of protocol vaccination used in ChAdOx1 nCoV-19.40, 41, 42 Here, we observed that vaccination with CoronaVac was able to induce 100% seroconversion, whereas 96.83% of ChAdOx1 nCoV-19–vaccinated subjects seroconverted. Furthermore, anti-RBD antibodies generated by ChAdOx1 nCoV-19 were higher compared with those generated by CoronaVac, especially for seropositive individuals.

Although available vaccines have already been shown to provide protection against severe COVID-19 and hospitalization,43,44 the decline in immunity over time,45 along with the emergence of SARS-CoV-2 variants, has led the scientific community to investigate the potential of different booster doses. Indeed, a significant decrease in protection in ChAdOx1 nCoV-19–immunized subjects is associated with the incidence of the Delta variant.1 A booster dose of BNT162b2 after a 2-dose regimen of BNT162b226 or ChAdOx1 nCoV-19 has already been shown to be safe and increases the neutralizing capacity of antibodies against SARS-CoV-2.46 Furthermore, a third dose of BNT162b2 after a full CoronaVac regimen caused a significant increase in anti-RBD IgG titers.39

Recent data also suggested that vaccination after previous infection could boost and extend immunity, leading to long-term protection (>1 year).47 Therefore, the preexisting response against SARS-CoV-2 must be well elucidated to determine the best strategy to be used in booster doses. Corroborating our findings, recent studies described the relevance of preexisting SARS-CoV-2 immunity and its impact on antibody response induced by mRNA-based vaccines including BNT162b2 and mRNA-1273,16, 17, 18,48 by ChAdOx1 nCoV-19,48 and also by CoronaVac8,49 vaccines. Subjects previously exposed to SARS-CoV-2 displayed higher levels of virus-specific antibodies after a single dose of BNT162b2. No significant difference was observed after the booster dose.50 Nonetheless, individuals previously exposed to SARS-CoV-2 displayed a more robust and long-lasting protection after 1 or 2 doses of the vaccine. In previously infected and vaccinated subjects, protection against symptomatic COVID-19 was similar to that reported after 2 doses followed by a booster.47 Together, both studies demonstrated the relevance of a booster dose for protection and suggest that previous infection boosts and extends immunity.

In summary, our results demonstrated that individuals with preexisting immunity to the SARS-CoV-2 developed higher antibody levels after a single dose. However, 2 doses are essential for unexposed individuals to achieve the same level. Previous infection-induced immunity against SARS-CoV-2 favors the development of a more robust immune response after vaccination. Our data highlighted the importance of a vaccine booster to increase the specific immune response to SARS-CoV-2.

Footnotes

This work was supported by Associação Fundo de Incentivo à Pesquisa, Fundação de Amparo à Pesquisa do Estado de São Paulo (grant no. 2021/13004-0). D.S.R. and M.L.A. are recipients of Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) fellowships.

Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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