COVID-19 Vaccination and Lethality Reduction: A Prospective Cohort Study in Venezuela

Abstract

Background
While rigorous randomized clinical trials have substantiated the efficacy of COVID-19 vaccines in reducing hospitalization and mortality rates, there is a paucity of post-authorization analyses conducted in real-world settings. In Venezuela, the primary vaccines administered are BBIBP-CorV (Sinopharm) and Gam-COVID-Vac (Sputnik-V). However, the performance and effectiveness of these vaccines within this specific population remain to be thoroughly investigated.

Methods
A prospective cohort study was undertaken from October 5, 2021, to March 31, 2022, across four sentinel hospitals in Venezuela. The outcomes were evaluated at two time points: day 28 and day 48, utilizing the WHO’s COVID-19 Clinical Progression Scale. For the purpose of analysis, patients were classified into two groups: vaccinated and unvaccinated.

Results
The study included a total of 175 patients, of which 85 (48.6%) were categorized as vaccinated, with the majority (76.5%) having received two doses. The median age of the patients was 68 years, with a slight predominance of females (53.1%), and the majority being unemployed/retired (60.6%). Hypertension (53.1%) and diabetes (18.3%) were the most prevalent comorbidities. The median Charlson index of the patients was 3 points, with no statistically significant differences observed between the groups (p = 0.2). Upon admission, dyspnea was more commonly observed in unvaccinated patients compared to vaccinated patients (76.7% vs. 62.4%, p = 0.039). Almost all laboratory parameters were comparable in both groups, with the exception of the median D-dimer level, which was significantly higher in unvaccinated patients (7.6 vs. 1.4 µg/mL, p = 0.015). A total of 50 patients (28.6%) died of the disease, with a higher proportion of deaths observed in unvaccinated patients compared to vaccinated patients (35.6% vs. 21.2%, p = 0.035). Factors such as advanced age (OR = 1.043, 95%CI = 1.015–1.071, p = 0.002) were associated with increased odds of death, while factors such as vaccination against COVID-19 (OR = 0.428, 95%CI = 0.185–0.99, p = 0.047), high oxygen saturation (OR = 0.964, 95%CI = 0.934–0.995, p = 0.024), and enoxaparin administration (OR = 0.292, 95%CI = 0.093–0.917, p = 0.035) were associated with decreased odds of death.

Conclusion
In the course of the third and fourth waves of the pandemic, vaccination against COVID-19 was found to be associated with a 57% reduction in lethality among patients treated in four public hospitals in Venezuela.

Full text

Page 1/19
COVID-19 Vaccination and Lethality Reduction: A Prospective
Cohort Study in Venezuela
David A. Forero-Peña (  vacter.cv@gmail.com )
Biomedical Research and Therapeutic Vaccines Institute
Jéssica L. Leyva
Biomedical Research and Therapeutic Vaccines Institute
María V. Valenzuela
Biomedical Research and Therapeutic Vaccines Institute
Óscar D. Omaña-Ávila
Biomedical Research and Therapeutic Vaccines Institute
Daniela L. Mendoza-Millán
Biomedical Research and Therapeutic Vaccines Institute
Elisanny A. Sánchez-Ytriago
“Dr. Luis Razetti” University Hospital
Andrea C. Lahoud-El Hachem
Biomedical Research and Therapeutic Vaccines Institute
Katherine R. Farro
“Dr. Luis Razetti” University Hospital
Ana K. Maita
“Dr. Luis Razetti” University Hospital
Romina del C. González
“Dr. Luis Razetti” University Hospital
Carlis M. Rodriguez-Saavedra
Biomedical Research and Therapeutic Vaccines Institute
Fernando Hernández-Medina
Venezuelan Scientic Research Institute, Altos de Pipe
Natasha A. Camejo-Ávila
Biomedical Research and Therapeutic Vaccines Institute
Diana C. Freitas-De Nobrega
Biomedical Research and Therapeutic Vaccines Institute
Rodrigo T. Celis
Central University of Venezuela
José L. Forero-Peña
Biomedical Research and Therapeutic Vaccines Institute
Alfonso Martínez
Central University of Venezuela
María E. Grillet
Central University of Venezuela
María E. Landaeta
University Hospital of Caracas
Fhabián S. Carrión-Nessi
Biomedical Research and Therapeutic Vaccines Institute
Research Article

Page 2/19
Keywords: COVID-19, Vaccination, COVID-19 Vaccines, Prospective Studies, Lethality, Venezuela
Posted Date: January 5th, 2024
DOI: https://doi.org/10.21203/rs.3.rs-3813947/v1
License:   This work is licensed under a Creative Commons Attribution 4.0 International License.  Read Full License
Additional Declarations: No competing interests reported.

Page 3/19
Abstract
Background
While rigorous randomized clinical trials have substantiated the ecacy of COVID-19 vaccines in reducing hospitalization and mortality
rates, there is a paucity of post-authorization analyses conducted in real-world settings. In Venezuela, the primary vaccines administered
are BBIBP-CorV (Sinopharm) and Gam-COVID-Vac (Sputnik-V). However, the performance and effectiveness of these vaccines within this
specic population remain to be thoroughly investigated.
Methods
A prospective cohort study was undertaken from October 5, 2021, to March 31, 2022, across four sentinel hospitals in Venezuela. The
outcomes were evaluated at two time points: day 28 and day 48, utilizing the WHO’s COVID-19 Clinical Progression Scale. For the
purpose of analysis, patients were classied into two groups: vaccinated and unvaccinated.
Results
The study included a total of 175 patients, of which 85 (48.6%) were categorized as vaccinated, with the majority (76.5%) having
received two doses. The median age of the patients was 68 years, with a slight predominance of females (53.1%), and the majority being
unemployed/retired (60.6%). Hypertension (53.1%) and diabetes (18.3%) were the most prevalent comorbidities. The median Charlson
index of the patients was 3 points, with no statistically signicant differences observed between the groups (
p
= 0.2). Upon admission,
dyspnea was more commonly observed in unvaccinated patients compared to vaccinated patients (76.7% vs. 62.4%,
p
= 0.039). Almost
all laboratory parameters were comparable in both groups, with the exception of the median D-dimer level, which was signicantly higher
in unvaccinated patients (7.6 vs. 1.4 µg/mL,
p
= 0.015). A total of 50 patients (28.6%) died of the disease, with a higher proportion of
deaths observed in unvaccinated patients compared to vaccinated patients (35.6% vs. 21.2%,
p
= 0.035). Factors such as advanced age
(OR = 1.043, 95%CI = 1.015–1.071,
p
= 0.002) were associated with increased odds of death, while factors such as vaccination against
COVID-19 (OR = 0.428, 95%CI = 0.185–0.99,
p
= 0.047), high oxygen saturation (OR = 0.964, 95%CI = 0.934–0.995,
p
= 0.024), and
enoxaparin administration (OR = 0.292, 95%CI = 0.093–0.917,
p
= 0.035) were associated with decreased odds of death.
Conclusion
In the course of the third and fourth waves of the pandemic, vaccination against COVID-19 was found to be associated with a 57%
reduction in lethality among patients treated in four public hospitals in Venezuela.
Background
As of December 27, 2023, the global impact of the coronavirus disease 2019 (COVID-19) has resulted in over 773million conrmed
cases and more than 6.9million deaths [1]. The initial impact of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was
signicant due to the limited understanding of its transmission, treatment, and prevention strategies [2]. In response to the pandemic,
numerous pharmaceutical companies initiated the development of vaccines against SARS-CoV-2, resulting in at least 78 conrmed
active vaccine candidates by April 2020 [3]. In late 2020, phase III results were reported for several vaccines, including BNT162b2 (Pzer-
BioNTech) with an ecacy of 90–97% [4, 5], mRNA-1273 (Moderna) with an ecacy of 87–97% [6], ChAdOx1-S/nCoV-19 (AstraZeneca)
with an ecacy of 65–88% [7], Gam-COVID-Vac (Sputnik-V) with an ecacy of 94–100% [8], CoronaVac (Sinovac) with an ecacy of
50–62%, and BBIBP-CorV (Sinopharm) with an ecacy of 64–86% [9]. The BNT162b2 and mRNA-1273 vaccines were the rst to receive
emergency use authorization from the US Food and Drug Administration (FDA) in December 2020 [10–12], followed by approval from
the World Health Organization (WHO) in January 2021 [13, 14]. The BBIBP-CorV and CoronaVac vaccines received approval in May 2021
[13, 15, 16]. However, other candidates such as Gam-COVID-Vac have yet to receive WHO approval [17–19].
Despite the slow progress of the vaccination process in Latin America, several countries have undertaken initiatives to expedite the
process. Mexico was the rst country to respond to the United Nations call in April 2021 to provide access to drugs and vaccines to
combat COVID-19 [20]. Colombia became the rst Latin American country to receive BNT162b2 vaccines under the COVID-19 Vaccines
Global Access (COVAX) program in March 2021 [21]. Chile donated 20,000 doses of the Chinese vaccine CoronaVac to Ecuador and

Page 4/19
Paraguay [22]. In Venezuela, the vaccination campaign against COVID-19 utilized BBIBP-CorV, CoronaVac, and Gam-COVID-Vac vaccines
due to agreements with the Russian Federation [23] and global collaboration mechanisms such as COVAX [24].
The Venezuelan government initially planned to launch the “Mass Vaccination Plan” in January 2021, but the rst batch of vaccines
arrived in February [25]. The process was divided into ve stages, with healthcare workers prioritized in the rst stage [24]. Subsequently,
the supply of vaccines to Venezuela continued sporadically and without prior planning, including the arrival of other vaccines such as
BBIBP-CorV, Gam-COVID-Vac, and vaccine candidates such as Abdala, Soberana-2, and EpiVacCorona [24, 26]. By September 2021, the
Pan American Health Organization (PAHO) reported a vaccination coverage of 14.9% in Venezuela. By May 2022, Venezuela had
administered a total of 38million doses, vaccinating 66% of its population [27]. Although some studies have demonstrated that Gam-
COVID-Vac vaccines are effective in eliciting a neutralizing antibody response in Venezuelan patients [28, 29], the clinical ecacy in this
population remains unknown.
While randomized clinical trials are considered the “gold standard” for evaluating the effects of a medical intervention, they have several
limitations, including sample size, subgroup analysis, restrictive inclusion criteria, and a highly controlled environment that may not be
replicated during a mass launch. In addition, patient inclusion is often based on their clinical stability [30]. Suboptimal adherence to
schedules and logistics also inuences its effectiveness. Therefore, post-authorization analyses are crucial for evaluating the actual
ecacy and behavior in real populations [31]. This study aims to describe the clinical behavior and outcome of vaccinated and
unvaccinated patients during the third and fourth pandemic waves in four hospitals in Venezuela.
Methods
Study design and population
A prospective cohort study was conducted including patients aged 18 and over who tested positive for SARS-CoV-2 infection and were
hospitalized between October 5, 2021, and March 31, 2022, at various sentinel hospitals in Venezuela. These included the University
Hospital of Caracas (Capital District), “Dr. Luis Razetti” University Hospital (Anzoategui state), “Ruiz y Páez” University Hospital Complex
(Bolivar state), and “Uyapar” Hospital (Bolivar state). The diagnosis of SARS-CoV-2 infection was conrmed via antigen testing and
reverse transcription polymerase chain reaction (RT-PCR) [32] at the “Rafael Rangel” National Institute of Hygiene (Venezuela). The study
period included cases from the third (June to December 2021) and fourth (January to February 2022) waves of the pandemic in
Venezuela [33], each characterized by different variants of SARS-CoV-2. A national genomic surveillance study analyzed samples from
nasopharyngeal or nasal swabs conrmed positive by RT-PCR during routine COVID-19 diagnosis in Venezuela. The third wave presented
variants of both interest and concern, starting with Gamma (B.1.1.248) and ending with Delta (B.1.617). The fourth wave was
predominantly characterized by the circulation of the Omicron variant (B.1.1.529) [34]. Patients with incomplete or illegible data on
variables of interest in interviews and medical records were excluded.
The severity of COVID-19 was categorized as mild (dened as the presence of various signs and symptoms of COVID-19, excluding
shortness of breath, dyspnea, or abnormal chest imaging), moderate (dened as evidence of lower respiratory disease during clinical
assessment or imaging and an oxygen saturation ≥ 94% on room air at sea level), severe (dened as oxygen saturation < 94% on room
air at sea level, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen < 300 mm Hg, a respiratory rate > 30
breaths/min, or lung inltrates > 50%), or critical (dened as respiratory failure, septic shock, and/or multiple organ dysfunction). These
categories were dened according to the guidelines provided by the National Institutes of Health (United States of America) [35].
Sample size
According to the Pan American Health Organization [36], as of October 4, 2021, there were 373,332 conrmed SARS-CoV-2 cases in
Venezuela. Hence, the sample size, with a 95% condence interval and a 5% margin of error, was at least 384 patients. The sampling
method was non-probabilistic.
Epidemiological and clinical assessment
Patient data were collected by trained staff at sentinel centers through interviews and review of medical records. This data included
epidemiological characteristics (such as age, sex, education level, marital status, race, occupation, domicile), clinical characteristics
(including symptoms on admission, pathological history, psychobiological habits, physical examination), paraclinical characteristics
(such as hematology, blood chemistry, coagulation tests), vaccination status against COVID-19 (veried by vaccination certicate issued
by the Venezuelan Ministry of Health), and treatment received for COVID-19 (including antivirals, antibiotics, antiparasitics,

Page 5/19
corticosteroids, thromboprophylaxis, immunomodulators, ventilatory support). The timely use of Remdesivir was dened as its
administration within 7 days following symptom onset, while the timely use of Favipiravir and Molnupiravir was dened as their
administration within 5 days following symptom onset. The appropriate use of Dexamethasone and Methylprednisolone was dened as
their administration for up to 10 days.
The Charlson Comorbidity index was calculated to predict patient lethality [37]. Patient outcomes was assessed at day 28 and 48 post-
admission using the WHO’s COVID-19 Clinical Progression Scale [38]. The dates of patients who died prior to evaluation were recorded.
For patients discharged alive prior to day 28 or 48, assessments were performed either face-to-face or via telephone to determine their
outcome. For the purpose of analysis, patients were classied into two groups based on their vaccination status: vaccinated and
unvaccinated. Individuals were dened as “vaccinated” if they had received at least one dose of a COVID-19 vaccine 14 days prior.
Statistical analysis
Patients’ data were summarized using descriptive statistics, including mean, standard deviation (SD), median, interquartile range (IQR),
frequency, and percentage (%). The distribution of numerical variables was evaluated using the Kolmogorov–Smirnov test. For variables
with a non-normal distribution, the Mann–Whitney U test was employed, while Student’s
t
-test was used for variables with a normal
distribution. Categorical variables were analyzed using Pearson’s chi-squared and Fisher’s exact tests. In instances where
post-hoc
analysis was required, the Bonferroni correction was applied to adjust the
p
-value. A
p
-value of less than 0.05 was considered
statistically signicant. Survival analysis was conducted using the Mantel–Cox test and visualized using Kaplan–Meier curves.
Binomial logistic regression with backward stepwise selection was utilized to identify factors associated with lethality. The most valid
model, which classied the highest percentage of patients and demonstrated a good t based on R2 Nagelkerke and the Hosmer–
Lemeshow test, was selected. Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) version
26 (International Business Machines Corporation, Armonk, NY, United States of America). Figures were generated using SPSS version 26
and Microsoft® Excel® version 2019 (Microsoft, Redmond, WA, United States of America).
Results
Patients’ sociodemographics
During the study period, a total of 175 patients were included: 59 (33.7%) captured at the University Hospital of Caracas, 43 (24.6%) at
the “Dr. Luis Razetti” University Hospital, 52 (29.7%) at the “Ruiz y Páez” University Hospital Complex, and 21 (12%) at the “Uyapar”
Hospital. Among these, 85 (48.6%) were categorized as vaccinated. Within the vaccinated group, 15/85 (17.6%) received one dose
(86.7% received BBIBP-CorV, and 13.3% received Gam-COVID-Vac), 65/85 (76.5%) received two doses (64.6% BBIBP-CorV, and 35.4%
Gam-COVID-Vac), and 5/85 (5.9%) received three doses (20% BBIBP-CorV, and 80% Gam-COVID-Vac) of the COVID-19 vaccine. All
patients reported receiving homologous vaccines. The mean duration between the onset of COVID-19 symptoms and the administration
of the last dose of the COVID-19 vaccine was 123.6 (SD 88.9) days.
The patients had a median age of 68 (IQR 28) years, with a majority being female (53.1%), of mestizo race (85.1%), and
unemployed/retired (60.6%) (Table1). Geographically, 67 (38.3%) patients resided in Bolivar state, 48 (27.4%) in Anzoategui state, 52
(29.8%) in the Metropolitan Area of Caracas, and the remaining 8 (4.5%) in other states. A signicant association was observed between
the categories “healthcare worker” and “vaccinated” (
p
= 0.0037).

Page 6/19
Table 1
Sociodemographic characteristics of patients with COVID-19 according to their vaccination status
Characteristics Total (
n
= 175, 100%) Vaccinated (
n
= 85, 48.6%) Unvaccinated (
n
= 90, 51.4%)
P
-value
Age, median (IQR), years 68 (28) 67 (27) 69 (24) 0.304*
Sex, female/male (%) 93/82 (53.1/46.9) 43/42 (50.6/49.4) 50/40 (55.6/44.4) 0.51†
Level of education,
n
(%)    0.002†
None 21 (12) 5 (5.9) 16 (17.8) 
Primary school 65 (37.1) 36 (42.4) 29 (32.2) 
High school 46 (26.3) 16 (18.8) 30 (33.3) 
Associate degree/University 43 (24.6) 28 (32.9) 15 (16.7) 
Marital status,
n
(%)    0.152‡
Married 68 (38.9) 39 (45.9) 29 (32.2) 
Single 64 (36.6) 32 (37.6) 32 (35.6) 
Widowed 29 (16.6) 10 (11.8) 19 (21.1) 
Divorced 8 (4.6) 2 (2.4) 6 (6.7) 
Cohabiting (common-law) 6 (3.4) 2 (2.4) 4 (4.4) 
Race,
n
(%)    0.045‡
Mestizo 149 (85.1) 74 (87.1) 75 (83.3) 
White 19 (10.9) 11 (12.9) 8 (8.9) 
Black 6 (3.4) 0 (0) 6 (6.7) 
Indigenous 1 (0.6) 0 (0) 1 (1.1) 
Occupation,
n
(%)    0.02†§
Unemployed/Retired 106 (60.6) 51 (60) 55 (61.1) 
Employed 29 (16.6) 15 (17.6) 14 (15.6) 
Self-employed 25 (14.3) 8 (9.4) 17 (18.9) 
Healthcare worker 11 (6.3) 10 (11.8) 1 (1.1) 
Student 4 (2.3) 1 (1.2) 3 (3.3) 
*Mann–Whitney U test; †Pearson’s chi-square; ‡Fisher’s exact test; §Signicant association only between “healthcare worker” and
“vaccinated” (
p
= 0.0037) for a value α = 0.005 by Bonferroni correction. IQR: interquartile range
Medical history
Less than 10% of all patients reported having at least one previous SARS-CoV-2 infection; this background was less frequent among the
unvaccinated compared to the vaccinated (4.4% vs. 14.1%,
p
= 0.026). Hypertension was the most common comorbidity, affecting 53.1%
(
n
= 93) of patients. This was followed by diabetes (18.3%,
n
= 32), and asthma (9.1%,
n
= 16). A total of 10 patients (5.7%) had a history
of oncologic conditions, including breast cancer (four patients), acute lymphoblastic leukemia (three patients), cervical cancer (one
patient), lung cancer (one patient), and thyroid cancer (one patient). Additionally, three patients (1.7%) were diagnosed with the human
immunodeciency virus. Interestingly, a higher proportion of vaccinated patients had asthma compared to unvaccinated patients (14.1%
vs. 4.4%,
p
= 0.026). The median Charlson index of patients was 3 (IQR 3) points, with no signicant differences observed between
groups (
p
= 0.2). Furthermore, no signicant differences were found between the vaccinated and unvaccinated patients in terms of
smoking habits, alcohol consumption, and illicit drug use (Table2).

Page 7/19
Table 2
Medical history of patients with COVID-19 according to their vaccination status
Characteristics Total (
n
= 175,
100%) Vaccinated (
n
= 85,
48.6%) Unvaccinated (
n
= 90,
51.4%)
P
-
value
Previous SARS-CoV-2 infection, yes
(%) 16 (9.1) 12 (14.1) 4 (4.4) 0.026*
Comorbidities, yes (%)    
Hypertension 93 (53.1) 40 (47.1) 53 (58.9) 0.117*
Diabetes 32 (18.3) 16 (18.8) 16 (17.8) 0.858*
Asthma 16 (9.1) 12 (14.1) 4 (4.4) 0.026*
COPD 10 (5.7) 4 (4.7) 6 (6.7) 0.576*
Cancer 10 (5.7) 3 (3.5) 7 (7.8) 0.226*
CKD 5 (2.9) 1 (1.2) 4 (4.4) 0.369†
Obesity 5 (2.9) 2 (2.4) 3 (3.3) 1†
CVD 4 (2.3) 2 (2.4) 2 (2.2) 1†
HIV 3 (1.7) 1 (1.2) 2 (2.2) 1†
Other 9 (5.1) 4 (4.7) 5 (5.6) 1†
Charlson Index, median (RIQ), points 3 (3) 2 (3) 3 (3) 0.2‡
Smoking, yes (%) 33 (18.9) 16 (18.8) 17 (18.9) 0.991*
Pack-year index, mean (SD) 17.7 (18.3) 21.8 (23.4) 13.8 (11.2) 0.215§
Alcoholics, yes (%) 23 (13.1) 13 (15.3) 10 (11.1) 0.413*
Illicit drug use, yes (%) 2 (1.1) 1 (1.2) 1 (1.1) 1†
*Pearson’s chi-square; †Fisher’s exact test; ‡Mann–Whitney U test; §Student’s
t
-test for independent samples. SARS-CoV-2: severe
acute respiratory syndrome coronavirus 2. COPD: chronic obstructive pulmonary disease. CKD: chronic kidney disease. CVD:
cerebrovascular disease. HIV: human immunodeciency virus. IQR: interquartile range. SD: standard deviation
Clinical characteristics upon admission
The median duration between the onset of COVID-19 symptoms and hospitalization was 6 (IQR 8) days, with no signicant differences
observed between the vaccinated and unvaccinated groups (7 vs. 5 days, respectively,
p
= 0.343 by Mann–Whitney U test). The most
common symptoms upon admission were fever (71.4%,
n
= 125), dyspnea (69.7%,
n
= 122), and dry cough (56.6%,
n
= 99). Less common
symptoms included low back pain (2.9%,
n
= 5), dysphonia (3.4%,
n
= 6), and dysphagia (4%,
n
= 7). A higher proportion of vaccinated
patients reported myalgias compared to unvaccinated patients (29.4% vs. 14.4%,
p
= 0.016), while dyspnea was more prevalent in
unvaccinated patients (76.7% vs. 62.4%,
p
= 0.039) (Fig.1).
Upon physical examination, the median heart rate, respiratory rate, and oxygen saturation at admission were 90 (IQR 24) bpm, 22 (IQR 6)
rpm, and 89 (IQR 14) %, respectively. Notably, the median respiratory rate was signicantly higher in unvaccinated patients compared to
vaccinated patients (24 vs. 22 rpm,
p
= 0.005). Crackles (73.1%,
n
= 128) and decreased breath sounds (50.3%,
n
= 88) were the most
common pathological ndings on chest auscultation, and altered consciousness was observed in 14.3% (
n
= 25) of all patients upon
admission. Furthermore, the most frequently documented radiographic thoracic pathological ndings were an interstitial pattern (51.7%,
n
= 62) and lung elds with a reinforced bronchovascular tract (20%,
n
= 24) (Table3).

Page 8/19
Table 3
Physical exam ndings on admission of patients with COVID-19 according to their vaccination status
Characteristics Total (
n
= 175,
100%) Vaccinated (
n
= 85,
48.6%) Unvaccinated (
n
= 90,
51.4%)
P
-value
Hemodynamic parameters    
Heart rate, median (IQR), bpm 90 (24) 88 (23) 90 (23) 0.916*‡
Breathing rate, median (IQR), rpm 22 (6) 22 (6) 24 (7) 0.004*‡
SBP, median (IQR), mm Hg 122 (30) 124 (30) 122 (29) 0.646*‡
DBP, median (IQR), mm Hg 75 (18) 75 (16) 76 (20) 0.821*‡
Oxygen saturation, median (IQR), % 89 (14) 90 (10) 87 (14) 0.02*‡
Chest pathologic ndings on auscultation,
yes (%)    
Crackles 128 (73.1) 63 (74.1) 65 (72.2) 0.777†*
Decreased breath sounds 88 (50.3) 44 (51.8) 44 (48.9) 0.704†*
Intercostal pull 23 (13.1) 13 (15.3) 10 (11.1) 0.413†*
Hypoexpansible chest 20 (11.4) 8 (9.4) 12 (13.3) 0.415†*
Roncus 18 (10.3) 11 (12.9) 7 (7.8) 0.261†*
Wheezing 16 (9.1) 10 (11.8) 6 (6.7) 0.242†*
Other 2 (1.1) 0 (0) 2 (2.2) 0.498‡†
Thoracic radiographic pathological ndings,
n
(%)    0.301‡†
Interstitial pattern 62 (51.7) 26 (44.8) 36 (58.1) 
Lung elds with reinforced bronchovascular
tract 24 (20) 16 (27.6) 8 (12.9) 
Inltrates 19 (15.8) 8 (13.8) 11 (17.7) 
Consolidation 10 (8.3) 5 (8.6) 5 (8.1) 
Pleural effusion 5 (4.2) 3 (5.2) 2 (3.2) 
Altered neurological status, yes (%) 25 (14.3) 14 (16.5) 11 (12.2) 0.422†*
*Mann–Whitney U test; †Pearson’s chi-square; ‡Fisher’s exact test. IQR: interquartile range. SBP: systolic blood pressure. DBP:
diastolic blood pressure
Paraclinical ndings upon admission
Table4 presents the paraclinical ndings of the patients upon admission. The majority of the laboratory parameters were comparable
between both groups. However, an exception was the median D-dimer level, which was signicantly higher in unvaccinated patients
compared to vaccinated patients (7.6 vs. 1.4 µg/mL,
p
= 0.015).

Page 9/19
Table 4
Paraclinical ndings on admission of patients with COVID-19 according to their vaccination status
Characteristics Total (
n
= 175,
100%) Vaccinated (
n
= 85,
48.6%) Unvaccinated (
n
= 90,
51.4%)
P
-
value
Hemoglobin, mean (SD), g/dL 12.2 (2.2) 12.5 (2.4) 12 (2) 0.212*
Hematocrit, mean (SD), % 39.9 (6.7) 38 (6.8) 37.8 (6.6) 0.85*
White blood cells, median (IQR),
×103/mL
9.4 (6.1) 10.2 (7.5) 8.9 (5.6) 0.097†
Neutrophils, median (IQR), ×103/mL 81 (18) 81 (15) 80.9 (18.5) 0.997†
Lymphocytes, median (IQR), ×103/mL 15 (14.8) 13.4 (12) 16.8 (17.3) 0.7†
Platelets, mean (SD), ×103/mL 245.5 (114.2) 254.6 (118.8) 236.1 (109.5) 0.39*
Glycemia, median (IQR), mg/dL 117 (69) 117 (70) 116.9 (70) 0.856†
Urea, median (IQR), mg/dL 36.5 (25.7) 38.5 (22) 36 (24.7) 0.729†
Creatinine, median (IQR), mg/dL 1 (0.4) 1 (0.4) 0.9 (0.5) 0.695†
PT, mean (SD), sec 12.4 (3.2) 12.3 (3.4) 12.4 (3.1) 0.905*
PTT, mean (SD), sec 30.5 (12.3) 32.4 (14.7) 28.1 (8.5) 0.312*
Fibrinogen, mean (SD), mg/dL 535.5 (454.6) 469.3 (232.9) 668.1 (742.7) 0.398*
AST, mean (SD), U/L 37.5 (17.6) 39 (19.4) 35.4 (15) 0.513*
ALT, mean (SD), U/L 40 (18.5) 40.6 (20.5) 39.1 (15.8) 0.808*
Total bilirubin, mean (SD), mg/dL 1 (1.1) 0.8 (0.6) 1 (1.4) 0.702*
LDH, mean (SD), U/L 430.8 (238.6) 438.5 (271) 423.1 (204.6) 0.783*
ESR, mean (SD), mm/h 41.5 (28.8) 31.4 (22.1) 51.5 (32.8) 0.204*
CRP, median (IQR), mg/L 12 (42.4) 14.7 (54.8) 11 (26.9) 0.134†
D-dimer, median (IQR), µg/mL 2.2 (14.3) 1.4 (3.9) 7.6 (118) 0.015†
Ferritin, median (IQR), ng/mL 336.1 (406.4) 405 (243.9) 314 (287.5) 0.222†
Procalcitonin, median (IQR), ng/mL 0.4 (0.6) 0.4 (1.6) 0.4 (0.2) 1†
Albumins, mean (SD), g/L 3.3 (0.5) 3.3 (0.5) 3.3 (0.6) 0.999*
*Student’s
t
-test for independent samples; †Mann–Whitney U test. SD: standard deviation. IQR: interquartile range. PT: prothrombin
time. PTT: partial thromboplastin time. AST: aspartate aminotransferase. ALT: alanine aminotransferase. LDH: lactate
dehydrogenase. ERS: erythrocyte sedimentation rate. CRP: C-reactive protein
Medications administered
In this cohort, the antivirals administered were Remdesivir (14.9%,
n
= 26), Favipiravir (4.7%,
n
= 13), and Molnupiravir (1.7%,
n
= 3). These
were administered in a timely manner in 50% (
n
= 13/26), 84.6% (
n
= 11/13), and 66.7% (
n
= 2/3) of cases, respectively. Furthermore,
45.7% (
n
= 80) of patients received antibiotic treatment, predominantly Levooxacin (23%), followed by Ceftriaxone and Meropenem.
Meropenem was administered in a higher proportion of vaccinated patients compared to unvaccinated patients (9.4% vs. 2.2%,
p
=
0.041). Regarding corticosteroids, Dexamethasone was administered to 59.4% (
n
= 104) of patients and was used appropriately in 88.2%
(n = 60/104) of these cases. Tocilizumab was only used in two patients (1.1%) (Supplementary Data 1).
Clinical outcome

Page 10/19
The median time between hospitalization and discharge was 10 (IQR 12) days, with no statistically signicant differences between the
vaccinated and non-vaccinated groups (11 vs. 10 days, respectively,
p
= 0.526 by Mann–Whitney U test). In the vaccinated group, two
patients required admission to the intensive care unit, whereas, in the unvaccinated group, four did (
p
= 0.683 by Pearson’s chi-square
test). During the study period, 50 (28.6%) patients died, and a higher proportion of deaths was found in unvaccinated patients compared
to vaccinated patients (35.6% vs. 21.2%,
p
= 0.035 by Pearson’s chi-squared test). Moreover, it was found that being vaccinated against
COVID-19 decreased the probability of death (
p
= 0.028) (Fig.2).
The median duration between hospitalization and discharge was 10 (IQR 12) days, with no signicant differences observed between the
vaccinated and unvaccinated groups (11 vs. 10 days, respectively,
p
= 0.526 by Mann–Whitney U test). In the vaccinated group, two
patients required admission to the intensive care unit, compared to four patients in the unvaccinated group (
p
= 0.683 by Pearson’s chi-
square test). During the study period, there were 50 deaths (28.6% of patients), with a higher proportion observed among unvaccinated
patients compared to vaccinated patients (35.6% vs. 21.2%,
p
= 0.035 by Pearson’s chi-squared test). Furthermore, it was determined that
vaccination against COVID-19 reduced the probability of death (
p
= 0.028) (Fig.2).
Factors associated with lethality
The most valid model (
p
< 0.001, R2 Nagelkerke = 0.341, Hosmer–Lemeshow test = 0.238) accurately classied 78.9% (
n
= 138) of
patients. Factors associated with increased odds of death included advanced age (OR = 1.043, 95% CI = 1.015–1.071,
p
= 0.002), and
receiving treatment at the “Dr. Luis Razetti” University Hospital (OR = 3.897, 95% CI = 1.053–14.418,
p
= 0.042) or “Uyapar” Hospital (OR =
7.317, 95% CI = 1.798–29.776,
p
= 0.005) compared to the University Hospital of Caracas. On the other hand, factors associated with
decreased odds of death included vaccination against COVID-19 (OR = 0.428, 95% CI = 0.185–0.99,
p
= 0.047), high oxygen saturation
(OR = 0.964, 95% CI = 0.934–0.995,
p
= 0.024), and administration of enoxaparin (OR = 0.292, 95% CI = 0.093–0.917,
p
= 0.035) (Table5).
Table 5
Factors associated with lethality patients with COVID-19
β
P
-value OR adjusted (95% condence interval)
Vaccinated against COVID-19, yes -0.848 0.047 0.428 (0.185–0.99)
Age 0.042 0.002 1.043 (1.015–1.071)
Sex, male 0.412 0.307 1.51 (0.687–3.326)
Care center (reference: University Hospital of Caracas)   
“Dr. Luis Razetti” University Hospital 1.36 0.042 3.897 (1.053–14.418)
“Ruiz y Páez” University Hospital Complex 0.874 0.103 2.397 (0.839–6.846)
“Uyapar” Hospital 1.99 0.005 7.317 (1.798–29.776)
Hypertension, yes -0.109 0.8 0.897 (0.386–2.083)
Dyspnea, yes -0.234 0.614 0.791 (0.318–1.967)
Oxygen saturation -0.037 0.024 0.964 (0.934–0.995)
Crackles, yes 0.447 0.375 1.563 (0.583–4.191)
Dexamethasone, yes -0.467 0.386 0.627 (0.218–1.803)
Enoxaparin, yes -1.231 0.035 0.292 (0.093–0.917)
Discussion
This study represents the rst multicenter research examining the clinical and epidemiological characteristics, including lethality rates,
among vaccinated and unvaccinated COVID-19 patients in Venezuela. Vaccination was correlated with a 57% decrease in lethality
relative to the unvaccinated cohort. The logistical challenges associated with vaccine distribution and storage in Venezuela were
mitigated through the assistance of international organizations such as the United Nations Children’s Fund, PAHO, and COVAX [24],
culminating in the vaccination of 66% of the population by May 2023 [27].

Page 11/19
A higher representation of healthcare workers was noted in the vaccinated group, likely attributable to this demographic being prioritized
for vaccination in accordance with WHO and PAHO guidelines for risk groups [32, 39]. Both the vaccinated and unvaccinated cohorts
had comparable characteristics in terms of sex, age, and comorbidities, with the exception of bronchial asthma. However, no signicant
differences were observed upon calculation of the Charlson Comorbidity Index for each group. Our study revealed a higher prevalence of
previous COVID-19 infections among vaccinated individuals when compared to the unvaccinated ones. One potential hypothesis for this
observation could be the risk of breakthrough infections following vaccination, particularly noted with inactivated whole virus vaccines
such as BBIBP-CorV [40, 41] and Gam-COVID-Vac [42]. Additionally, vaccine hesitancy, often accompanied by a denial of the virus’s
existence or the severity of the disease, may contribute to underreporting of infection rates within the unvaccinated population [43]. The
most prevalent symptoms and signs, including dyspnea, fever, dry cough, tachypnea, and decreased oxygen saturation, were consistent
with previous studies [44–55]. Unvaccinated patients had a higher prevalence of dyspnea, increased respiratory rate, and lower oxygen
saturation values, corroborating ndings from similar studies [56–60]. Interestingly, despite a higher incidence of asthma in the
vaccinated group, this comorbidity has been linked to reduced lethality in hospitalized patients due to its association with TH2
lymphocyte inammation, which acts as a protective factor against COVID-19 [61–65]. Consistent with prior documentation [66, 67], D-
dimer values at admission showed statistically signicant differences between the groups, with higher levels observed in the
unvaccinated group, indicative of a hypercoagulable state and increased risk of adverse events and death.
This study demonstrated a reduction in COVID-19 lethality among patients vaccinated with BBIBP-CorV and Gam-COVID-Vac, consistent
with similar studies conducted in Qatar [68] and India [69] that reported a more than threefold increase in lethality among unvaccinated
patients. Prior researches have evaluated the ecacy of the BNT162b2, mRNA-1273, CoronaVac, and Gam-COVID-Vac vaccines,
concluding that they are all safe and effective against all variants of interest included in their work in several countries around the world,
including Chile, Brazil, Colombia, and Ecuador [70–73]. However, the quality of evidence varied across vaccines [74]. A study conducted
in China involving the Delta variant demonstrated effective protection following two doses of inactivated virus vaccines such as BBIBP-
CorV and CoronaVac, while partial vaccination offered no signicant protection [75]. Another multicenter case-control study carried out in
South American countries such as Argentina, Colombia, Chile, and Brazil, evaluated the ecacy of the CoronaVac, BBIBP-CorV, and Gam-
COVID-Vac vaccines (among others) by age and by the predominant circulating variant of SARS-CoV-2, demonstrating that vaccines
prevented hospitalizations and deaths even among the oldest population [76, 77]. In a multicenter United States study, progression to
death after COVID-19 hospitalization was associated with a lower likelihood of vaccination (OR = 0.41; 95% CI = 0.19–0.88) [72]. Finally,
a study in Pakistan found signicantly higher percent deaths in the unvaccinated group compared to the vaccinated group. However,
they also documented variations according to patient age and type of vaccine. For example, the percent of COVID-19 cases who died
among unvaccinated individuals > 50 years of age was 3.83- and 7.49-fold higher compared to recipients of BBIBP-CorV and Gam-
COVID-Vac, respectively [78]. This is similar to our results.
High oxygen saturation, a valuable metric for classifying disease severity, was associated with lower lethality rates in both groups under
study. Conversely, low oxygen saturation has been identied as a signicant indicator of death risk [51, 79]. Additionally, the
administration of enoxaparin, a low molecular weight heparin, was found to decrease lethality risk within our cohort, consistent with
previous research [80, 81]. The impact of low molecular weight heparins in COVID-19 varies signicantly depending on whether
thromboprophylaxis or therapeutic doses are used, with the latter demonstrating greater benet [82]. However, in accordance with the
guidelines of the “Ministerio del Poder Popular para la Salud” (the primary national health institute) in Venezuela during the time of our
study [83], thromboprophylaxis dosage was employed in this population, still yielding a signicant difference.
In our model, no signicant association was observed between comorbidities and COVID-19 outcomes, contradicting previous ndings
[84, 85]. The Charlson Comorbidity Index enabled us to evaluate patients in both groups based on their number of comorbidities and risk.
However, well-managed long-term pathologies could potentially inuence the accuracy of this measure and the outcomes. Increased age
was associated with a higher risk of death, potentially due to older patients’ susceptibility to COVID-19 as hypothesized by Ayón-Aguilar
et al
. [86], which could be attributed to immunosenescence and their dysregulated inammatory response. Institutions should consider
assessing frailty at admission for all older patients admitted with COVID-19 to provide appropriate care for this risk group.
Signicant variations in death risk were observed across different care centers. The therapeutic management of COVID-19 initially
presented an uncertain pathway for providers, and guidelines remained quite open for personal suggestions and individualized treatment
adapted on a case-by-case basis [83]. Coupled with the disparities described in healthcare centers in Venezuela, including challenges
such as access to basic needs like water supply, continuous electricity, personnel shortage, and medication availability [87, 88], these
factors do not remain constant between centers and departments within the same institution. The University Hospital of Caracas,

Page 12/19
located in the country’s capital, may have had an advantage in terms of resource accessibility and allocation, resulting in better
outcomes and highlighting the ethical dilemma in attention care in Venezuela.
This study represents the rst nationwide analysis of the impact of vaccination on lethality rates among patients with COVID-19 in
Venezuela. It encompasses a comparative assessment of hospitalized individuals who have received the vaccine and those who have
not from four different hospitals during two separate waves of the pandemic within the country. Institutional variables, such as
availability of beds and medical supplies, accessibility to diagnostic procedures, and level of patient care, elucidate the Venezuelan
healthcare landscape. These elements contribute to a more accurate description of vaccine ecacy under real-world conditions.
However, this study has several limitations. Despite its multicenter nature, it only included four hospitals in major cities of the country, so
the results should be extrapolated with caution, especially in sociodemographic contexts of peri-urban and rural regions. The sample
size was limited. This limitation is attributable to several factors: primarily, the restricted availability of beds within the COVID-19
designated areas of the participating hospitals, notably at the “Dr. Luis Razetti” University Hospital and “Uyapar” Hospital; secondarily,
the protracted hospital stays required for severe cases, which inherently reduced the turnover of patient admissions; and lastly, the
limited access to antigen and RT-PCR testing for SARS-CoV-2 detection, with pronounced scarcity at the “Ruiz y Páez” University Hospital
Complex and “Uyapar” Hospital. As a result, patients who could not have their infection conclusively veried due to these testing
limitations were excluded from the study. Furthermore, its non-random methodology limits the estimation of vaccine ecacy, and the
small sample size does not allow for secondary analysis in the population that received a partial vaccination schedule or a booster dose,
nor does it allow for understanding the individual ecacy of each type of vaccine. In some cases, follow-up was conducted via
telephone, but it was not possible in three patients, so the lethality found in this work could be higher. Finally, the absence of molecular
tools did not allow for determining the variants involved in each case, which constitutes a signicant limitation since we know that they
may modify patient outcomes [89, 90]. This study posited that notwithstanding suboptimal adherence to vaccination schedules and
logistical challenges in Venezuela, the deployment of COVID-19 vaccines contributed to a decrease in lethality rates among infected
individuals. Employing a prospective, multicenter methodology, the study assessed the clinical outcomes of patients hospitalized for
COVID-19. The ndings revealed that, regardless of the vaccine variant administered, there was a notable reduction in the lethality rate,
greater than 50%, among the cohort of vaccinated individuals. This nding marks a signicant advancement in comprehending the
ramications of immunization within practical environments and could provide critical insights for public health policy formulation.
Nonetheless, further research involving a more extensive and randomly sampled populace is imperative to facilitate nuanced analyses
contingent upon the vaccine type and dosage received. Moreover, the inclusion of patients from hospitals across diverse demographic
and healthcare landscapes is recommended to permit the analysis of additional variables unique to each medical facility.
Conclusions
This study found an association between COVID-19 vaccination and a reduction in lethality among COVID-19 patients treated in four
public hospitals in Venezuela during the third and fourth pandemic waves. However, to ascertain the individual ecacy of each vaccine
and its correlation with the number of doses administered, further multicenter studies involving larger populations are warranted.
Abbreviations
COVID-19
coronavirus disease 2019,
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2,
FDA
US Food and Drug
Administration,
WHO
World Health Organization,
COVAX
COVID-19 Vaccines Global Access,
PAHO
Pan American Health Organization,
RT-PCR
reverse transcription polymerase chain reaction,
SD
standard deviation,
IQR
interquartile range,
SPSS
Statistical Package for the
Social Sciences
Declarations
Ethics approval and consent to participate
The study protocol was reviewed and approved by the Independent Bioethics Committee for Research of the National Center for
Bioethics (CIBI-CENABI, in Spanish) of Venezuela (CIBI-CENABI-14/2021). The study was conducted in accordance with the ethical
principles for medical research in humans of the Declaration of Helsinki and the Venezuelan regulations for this type of research. Signed
informed consent was requested from all patients at the beginning of hospitalization in the COVID-19 ward.
Consent for publication

Page 13/19
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in the article.
Competing interests
The authors declare no competing interests.
Funding
This research did not receive any specic grant from funding agencies in the public, commercial, or not-for-prot sectors.
Authors’ contributions
DAFP, JLL, MVV, and FSCN conceived and designed the study. DAFP, JLL, MVV, DCFDN, EAS, KRF, AKM, RdCG, DLMM, and FSCN
collected clinical data. ÓDOÁ, ACLEH, CMRS, FHM, NACÁ, DLMM, and FSCN analyzed and interpreted the data. JLL, MVV, ÓDOÁ, ACLEH,
CMRS, RTC, JLFP, DLMM, AM, and FSCN wrote the manuscript. DAFP, FHM, MEG, JE, MEL, and FSCN critically reviewed the manuscript.
All authors reviewed and approved the nal version of the manuscript.
Acknowledgements
Not applicable.
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Figures

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Figure 1
Symptoms on admission of patients with COVID-19 according to their vaccination status. Data are graphed as percentage. *
p
< 0.05 (
p
‐
values by Pearson’s chi-square)

Page 19/19
Figure 2
Kaplan-Meier curves showing the probability of survival patients with COVID-19 according to their vaccination status.Log Rank (Mantel–
Cox test) = 4.811,
p
= 0.028.
Supplementary Files
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SupplementaryData1.docx