Vaccines | Free Full-Text | Differences in the Evolution of Clinical, Biochemical, and Hematological Indicators in Hospitalized Patients with COVID-19 According to Their Vaccination Scheme: A Cohort Study in One of the World’s Highest Hospital Mortality Populations
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1. Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease (COVID-19), a genuinely multisystemic illness despite its primary impact on the respiratory system [1,2]. While most infections are self-limiting or necessitate ambulatory care, 20% of symptomatic, unvaccinated adults may require hospitalization [2]. Vaccination has been shown to reduce this hospitalization rate by up to 10 times [3,4]. Regional and country-specific factors can influence the proportion of patients developing severe/critical COVID-19 and requiring hospitalization [5].
During the initial years of the pandemic, various types of COVID-19 vaccines were developed. The most widely distributed include: (1) mRNA-based vaccines such as BNT162b2 (Pfizer—BioNTech) and mRNA-1273 (Moderna—NIAID); (2) adenoviral vector-based vaccines like ChAdOx1-S (Oxford—AstraZeneca), Ad26.COV2.S (Johnson & Johnson), Gam-COVID-Vac (Gamaleya), and Ad5nCoV (CanSino); and (3) inactivated coronavirus-based vaccines like CorovaVac (Sinovac) and BBIBP-CorV (Sinopharm) [1,3,6,7]. From a global public health perspective, the primary and extensively studied benefit of vaccines is their efficacy in preventing disease or severe outcomes (reducing hospitalizations), ranging from 70 to 95% [3], varying based on the population and the investigated vaccine type [3].
When vaccination fails to prevent hospitalization in vaccinated individuals, an understudied scenario arises, and existing reports contradict whether being vaccinated modifies the mortality of these patients [7,8,9,10,11,12]. Additionally, how vaccines alter the clinical course and predictors of death in patients with severe/critical COVID-19 remains unknown. This is a pertinent topic that may vary not only with the type of vaccine but also in the context of the analyzed population. Mortality in hospitalized COVID-19 patients worldwide has varied from 1% to 52% [13], greatly influenced by the pandemic’s temporality, ethnic and sociocultural characteristics of each population, and the diverse therapeutic strategies applied in different regions [14].
From March 2020 to August 2022, in Mexico, the overall hospital case fatality rate was 45.1% (95% CI 44.9, 45.3), with variations depending on the pandemic period, reaching a maximum peak of 50.8% overall [6], including a peak mortality rate of 60% in hospitalized individuals aged 60 or older [6]. This places Mexico among the populations with the highest mortality in hospitalized COVID-19 patients globally. In this challenging population context, a cohort study was conducted to understand the effects of administering different types of vaccines on the clinical evolution of hospitalized patients and whether such vaccines induce changes capable of modifying the risk of death.
4. Discussion
In the context of a population with one of the highest mortality rates worldwide for COVID-19 hospitalized patients, there were differences in the proportion of deaths based on the vaccination scheme. Those who died in higher proportion were the unvaccinated (52.6%), followed by those vaccinated with ChAdOx1-S (41.1%) and those vaccinated with BNT162b2 (31.7%) (vaccination schemes with at least two doses and at least 14 days elapsed since their second dose). The lower mortality of those vaccinated with BNT162b2 occurred even though these patients were older and had higher severity (higher PSI) at the time of hospital admission. Those vaccinated with ChAdOx1-S or BNT162b2 had nearly half the risk of dying from the disease compared to the unvaccinated (adjusted RR 0.54, 95% CI 0.30–0.97, p = 0.041). However, when stratifying by vaccine type, those vaccinated with BNT162b2 had 2.4-times less risk of death compared to the unvaccinated (adjusted RR 0.41, CI95% 0.2–0.8, p = 0.008), while those vaccinated with ChAdOx1-S did not differ from the unvaccinated in terms of their risk of death (adjusted RR 1.04, CI95% 0.5–2.3, p = 0.915). This suggests differences in the clinical outcomes of patients based on the administered vaccine.
The reduction in the risk of death by vaccination in hospitalized COVID-19 patients aligns with previous reports from Croatia [8] and Argentina-Spain [7]. However, other studies have not shown differences in mortality between vaccinated and unvaccinated patients in populations from the United States [9], Israel [10], or France [11]. Even a study conducted in Poland suggests that hospitalized patients may have a higher mortality after receiving one or two vaccine doses [12]. Huespe IA et al. (2023) mention that these contradictory results may be due to confounding variables, especially differences in the proportion and severity of comorbidities, generally higher in vaccinated groups at the beginning of the pandemic [7]. Differences among subgroups of populations can also lead to variations in the immune response to vaccines, which is progressively lower with older age and a higher prevalence of comorbidities [29].
Among studies that have found that vaccination reduces mortality in hospitalized patients, one points out that those vaccinated with ChAdOx1-S (and other vaccines with adenoviral vectors) have lower mortality than those vaccinated with BNT162b2 [8], while another observed that those vaccinated with BNT162b2 had a greater reduction in mortality (OR 0.37; 95% CI: 0.23–0.59), followed by those vaccinated with ChAdOx1-S (OR 0.42; 95% CI: 0.20–0.86) [7]. In the first study, Busic et al. (2022) discuss that those vaccinated with BNT162b2 could have higher mortality than those vaccinated with ChAdOx1-S because mRNA vaccines (such as Pfizer—BioNTech) were the first vaccines to be administered, having preference for the older population and among selected patients with unfavorable prognostic characteristics [7,8]. In the present report from Mexico, something similar happened in the vaccination strategy, with older patients and those with a higher index of comorbidities initially vaccinated and using BNT162b2. Therefore, patients vaccinated with BNT162b2 had more adverse characteristics and higher severity at the time of hospital admission, especially during periods when the Delta variant was one of the predominant strains in the population (see Figure 2). However, even with a worse prognosis, those vaccinated with BNT162b2 had lower mortality in absolute numbers. In the analysis adjusting for variables such as age, sex, morbidity, severity, as well as, the pandemic period to consider variations in different waves (as a random effect), it was found that those vaccinated with BNT162b2 reduce the risk of death by 2.4-times compared to the unvaccinated, while those vaccinated with ChAdOx1-S did not differ from the unvaccinated ones in adjusted risk of death (see Table 4). However, as mentioned above, both those vaccinated with ChAdOx1-S and BNT162b2 reduce the overall percentage of death compared to those not vaccinated (41.1%, 31.7%, and 52.6%, respectively).
In hospitalized patients, it was observed that receiving either the ChAdOx1-S or BNT162b2 vaccine contributes to higher lymphocyte counts and lower Platelet-to-Lymphocyte Ratios (PLR) compared to the unvaccinated group (Figure 4, Table 2, Table 7 and Table 9). Vaccination prevented severe hypoxemia from being the most sensitive and specific factor for predicting death, as observed in the unvaccinated group. This aligns to the improved survival rates found in both vaccinated groups. It is noteworthy that in the vaccinated individuals, neutrophilia serves as a predictive factor for death, suggesting that a concomitant bacterial infection might be a relevant factor leading to mortality in the vaccinated group. However, individuals vaccinated with BNT162b2 have a lower risk of death than those vaccinated with ChAdOx1-S (Table 5). This may be attributed to the additional observation that, on average, individuals vaccinated with BNT162b2 exhibit less impairment in markers of hepatic damage, lower levels of certain inflammatory markers (such as serum ferritin), and lower levels of D-dimer compared to those vaccinated with ChAdOx1-S or the unvaccinated group.
The vaccines appear to induce a more robust immune response against severe/critical COVID-19 infection, leading to increased survival. The results suggest that more severe damage to other organs or systems, in addition to the lungs, would be necessary to predict death in vaccinated patients (Table 8, Table 9 and Table S1). However, the ChAdOx1-S vaccine has a less beneficial effect than BNT162b2 in hospitalized patients. One possible explanation for this could be a lower stimulation of the immune system against COVID-19, resulting in lower survival rates in severe patients. It has been previously demonstrated that the efficacy for preventing disease or severe disease is higher for BNT162b2 compared to ChAdOx1-S (95–87.5% vs. 70%, respectively) [3], which aligns with a lower neutralization of SARS-CoV-2 by serum from individuals vaccinated with ChAdOx1-S compared to serum from BNT162b2-vaccinated individuals [3]. Another potential cause could be that using an adenoviral vector as a vehicle to stimulate immunity may limit some vaccine benefits. Exposure to adenovirus in preclinical models has led to long-term effects, including adverse metabolic, morphological (hepatic), and functional changes, with significantly high levels of serum inflammation markers [30,31]. It has been postulated that these chronic adenoviral effects, including prolonged inflammatory responses [32,33], could occur with their application in gene therapy [30] or after their use in COVID-19 vaccines [34]. However, these are unverified hypotheses that need to be investigated in future research, as the emergency authorization of COVID-19 vaccines (adenoviral or mRNA) may not have fully addressed certain safety aspects [32,35].
A strength of the present study was the adjustment for comorbidities, severity, and other relevant factors that can affect the death prognosis of patients, as well as the analysis with repeated measurements of various clinical factors during hospitalization. Additionally, the temporality of the pandemic (month of hospital admission) was considered in the statistical model used. Another relevant aspect is that the effect of vaccination was analyzed from different points of view (mortality rate, survival curves, association analysis, ROC curves, evaluation of hematological and biochemical parameters), so conclusions can be reached based multiple aspects and not with the result of a single analysis. Undoubtedly, evaluating the effect of vaccination in a population of hospitalized patients with high mortality helps assess the potential impact of vaccines under very adverse prognostic conditions, which is challenging to evaluate in other populations or periods of the pandemic.
Considering the results obtained in this study, it is imperative to highlight that these findings reinforce the efficacy of COVID-19 vaccines in reducing hospital fatalities, in addition to the previously reported reduction in severity and hospitalizations [3,4]. However, addressing these findings with caution is fundamental to avoid misinterpretations that could be misused for anti-vaccine purposes. It is crucial to emphasize that this study not only highlights a significant decrease in the risk of mortality for vaccinated individuals, especially in populations with increased health risks, but also underscores notable differences among the various types of vaccines used. The findings highlight the crucial and beneficial role of vaccination, adding to what was previously described to reduce symptoms and the risks of hospital admission and death [36,37]. These collective results underscore the current importance of vaccination efforts, considering variations in populations and the types of vaccines used.
The present study also had limitations. The number of patients did not allow for evaluations and comparisons between patients with a single vaccine dose. Similarly, the mortality in patients vaccinated with ChAdOx1-S was intermediate between the unvaccinated and those vaccinated with BNT162b2, so in various analyses, statistically significant differences between ChAdOx1-S and the other two groups were not observed. Future analyses with a larger number of individuals are desirable to better observe the differences between these groups. Additional facets of the investigation pertinent to the studied population, such as the types of vaccines administered and who was given priority for vaccination at the beginning of the pandemic in Mexico, did not allow for the evaluation of other vaccine brands and types as well as their effects on various population strata with fewer comorbidities. Likewise, only 8.9% of the hospitalized patients included had a booster vaccine, making a detailed analysis of this subgroup unfeasible. It is important to note that exploring this aspect was limited in the current study. Future research efforts should consider a more in-depth examination of this subgroup, especially in the context of different COVID variants.
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