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International Journal of Infectious Diseases 126 (2023) 164–173
Contents lists available at ScienceDirect
International Journal of Infectious Diseases
journal homepage: www.elsevier.com/locate/ijid
Open-label phase I/II clinical trial of SARS-CoV-2 receptor binding
domain-tetanus toxoid conjugate vaccine (FINLAY-FR-2) in
combination with receptor binding domain-protein vaccine
(FINLAY-FR-1A) in children
Rinaldo Puga-Gómez
1 , 2 , #
, Yariset Ricardo-Delgado
1 , #
, Chaumey Rojas-Iriarte
3
,
Leyanis Céspedes-Henriquez
4
, Misleidys Piedra-Bello
1
, Dania Vega-Mendoza
1
,
Noelvia Pestana Pérez
1
, Beatriz Paredes-Moreno
5
, Meiby Rodríguez-González
5
,
Carmen Valenzuela-Silva
6
, Belinda Sánchez-Ramírez
7
, Laura Rodríguez-Noda
5
,
Rocmira Pérez-Nicado
5
, Raul González-Mugica
5
, Tays Hernández-García
7
,
Talía Fundora-Barrios
7
, Martha Dubet Echevarría
8
, Juliet María Enriquez-Puertas
8
,
Yenicet Infante-Hernández
8
, Ariel Palenzuela-Díaz
9
, Evelyn Gato-Orozco
9
,
Yanet Chappi-Estévez
10
, Julio Cesar Francisco-Pérez
11
, Miladi Suarez-Martinez
4
,
Ismavy C. Castillo-Quintana
5
, Sonsire Fernandez-Castillo
5
, Yanet Climent-Ruiz
5
,
Darielys Santana-Mederos
5
, Yanelda García-Vega
7
, María Eugenia Toledo-Romani
12
,
Delaram Doroud
13
, Alireza Biglari
13
, Yury Valdés-Balbín
5
, Dagmar García-Rivera
5 , # , ∗,
Vicente Vérez-Bencomo
5
, SOBERANA Research Group
1
1
Pediatric Hospital “Juan Manuel Marquez,” Havana, Cuba
2
Central Clinic “Cira García”, La Habana, Cuba
3
Policlinic “5 de Septiembre”, La Habana, Cuba
4
Policlinic “Carlos J. Finlay”, La Habana, Cuba
5
Finlay Vaccine Institute, Havana, Cuba
6
Cybernetics, Mathematics, and Physics Institute, La Habana, Cuba
7
Centre of Molecular Immunology, Havana, Cuba
8
National Civil Defense Research Laboratory, Mayabeque, Cuba
9
Centre for Immunoassays, La Habana, Cuba
10
National Clinical Trials Coordinating Center, Havana, Cuba
11
Pediatric Hospital “Borrás-Marfán”, La Habana, Cuba
12
“Pedro Kourí” Tropical Medicine Institute, Habana, Cuba
13
Pasteur Institute of Iran, Te hra n, Islamic Repub lic of Iran
a r t i c l e i n f o
Article history:
Received 17 March 2022
Revised 16 October 2022
Accepted 12 November 2022
a b s t r a c t
Objectives: To evaluate a heterologous vaccination scheme in children 3-18 years old (y/o) combining two
SARS-CoV-2r- receptor binding domain (RBD)protein vaccines.
Methods: A phase I/II open-label, adaptive, and multicenter trial evaluated the safety and immunogenic-
ity of two doses of FINLAY-FR-2 (subsequently called SOBERANA 02) and the third heterologous dose
∗Corresponding author.
E-mail address: dagarcia@finlay.edu.cu (D. García-Rivera) .
# These authors contributed equally.
1 SOBERANA Research Group: María Elena Mesa-Herrera
1
, Yarmi la García-Cristiá1
, Leonor Verdecia-Sánchez
1
, Rafael del Valle Rodríguez
1
, Yudalvies Oquendo-de la
Cruz
1
, Daysi Álvarez-Montalvo
1
, Randy Grillo-Fortún
1
, Liset López-González
1
, Omaida Fonte Galindo
4
, Yes en i Reyes-González
4
, Ana Beatriz González-Álvarez
4
, Linet Gorrita-
Mora
4
, Rodrigo Valera-Fernández
5
, Ivis Ontivero-Pino
5
, Marisel Martínez-Pérez
5
, Esperanza Caballero-Gonzalez
5
, Aniurka Garcés-Hechavarría
5
, Dayle Martínez-Bedoya
5
, Maite
Medina-Nápoles
5
, Yeney Regla Domínguez-Pentón
5
, Yadira Cazañas-Quintana
7
, Thais Fundora Barrios
7
, Diana R. Hernández Fernández
7
, Gretchen Bergado-Báez
7
, Ivette Orosa-
Vazquez
7
, Franciscary Pi-Estopiñan
7
, Marianniz Díaz-Hernández
7
, Otto Cruz-Sui
8
, Enrique Noa-Romero
8
, Arilia García-López
10
, Sandra Rivadereira Muro
10 Gerardo Baro-
Roman
9
https://doi.org/10.1016/j.ijid.2022.11.016
1201-9712/© 2022 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND
license (
http://creativecommons.org/licenses/by-nc-nd/4.0/ )
R. Puga-Gómez, Y. Ricardo-Delgado, C. Rojas-Iriarte et al. International Journal of Infectious Diseases 126 (2023) 16 4– 173
Keywo rds:
COVID-19
SARS-CoV-2
Conjugate vaccine
Pediatric vaccine
Heterologous scheme
Subunit vaccine
RBD vaccine
of FINLAY-FR-1A (subsequently called SOBERANA Plus) in 350 children 3-18 y/o in Havana Cuba. Pri-
mary outcomes were safety (phase I) and safety/immunogenicity (phase II) measured by anti-RBD im-
munoglobulin (Ig)G enzyme-linked immunoassay (ELISA), molecular and live-virus neutralization titers,
and specific T-cells response. A comparison with adult immunogenicity and predictions of efficacy were
made based on immunological results.
Results: Local pain was the unique adverse event with frequency > 10%, and none was serious neither
severe. Two doses of FINLAY-FR-2 elicited a humoral immune response similar to natural infection; the
third dose with FINLAY-FR-1A increased the response in all children, similar to that achieved in vacci-
nated young adults. The geometric mean (GMT) neutralizing titer was 173. 8 (95% confidence interval [CI]
131.7; 229.5) vs Alpha, 142 (95% CI 101.3; 198.9) vs Delta, 24.8 (95% CI 16.8; 36.6) vs Beta and 99.2 (95%
CI 67.8; 145.4) vs Omicron.
Conclusion: The heterologous scheme was safe and immunogenic in children 3-18 y/o.
Trial registry: https://rpcec.sld.cu/trials/RPCEC0 0 0 0 0374
©2022 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious
Diseases.
This is an open access article under the CC BY-NC-ND license
( http://creativecommons.org/licenses/by-nc-nd/4.0/ )
Introduction
Protecting children against COVID-19 is pivotal for control-
ling virus dissemination and reducing disease incidence. COVID-19
cases and hospitalizations among children and adolescents, firstly
driven by the Delta variant and recently by Omicron, have risen
sharply, even in countries with high adult vaccination coverage
( Delahoy et al., 2021 ; Elliott et al., 2022 ). This context has accel-
erated the clinical trials of anti-SARS-CoV-2 vaccines for children
( Ali et al., 2021 ; Frenck et al., 2021 ; Han et al., 2021 ; Wallace et
al., 2021 ; Walter et al., 2021; Xia et al., 2022 ).
For more than 30 years, the Finlay Vaccine Institute has
produced tetanus toxoid-conjugated vaccines applied to children
worldwide; their safety has been extensively proven through hun-
dreds of millions of doses ( Huang and Wu, 2010 ; Verez-Bencomo
et al., 2004 ). FINLAY-FR-2 (also called SOBERANA 02) immunogen
is an anti-SARS-CoV-2 recombinant receptor binding domain (RBD)
conjugated to tetanus toxoid ( Valdes-Balbin et al., 2021a , 2021b ).
It is the unique conjugate vaccine in World Health Organization’s
vaccines pipeline ( World Health Organization, 2021 ). T-cell epi-
topes present in tetanus toxoid were expected to promote RBD-
specific B- and T-cell memory, high affinity and longstanding RBD
IgG antibodies.
SOBERANA 02 has proved its safety and immunogenicity in
adults 19-80 years old (y/o); after two doses, its efficacy was
69.7%. Combined with the third dose of FINLAY-FR-1A (also called
SOBERANA Plus) (recombinant RBD dimer vaccine) in a three-dose
heterologous scheme, efficacy increased to 92.0% (Eugenia-Toledo-
Romaní et al., 2021, 2022a, 2022b ). In August 2021, the Cuban
Regulatory Authority granted their emergency use authorization
in adults, being since then extensively applied nationally for pre-
venting COVID-19 in Cuba ( Cuban and National Regulatory Agency,
2021 ).
Here, we report the results of an open-label phase I/II clinical
trial in children 3-18 y/o to evaluate the safety and immunogenic-
ity of two doses of FINLAY-FR-2 and the third dose of FINLAY-FR-
1A. We avoided a placebo-controlled trial in this age group due to
ethical concerns ( Dal-Ré and Caplan, 2021 ); alternatively, a recom-
mended comparison (or immunobridging) with an adult
´
s immuno-
genicity was established ( US Food and Drug Administration [FDA],
2021 ) and the clinical efficacy was estimated based on immuno-
logical results.
Method
Study design
We designed a phase I/II study, open-label, adaptive and mul-
ticenter to evaluate the safety, reactogenicity, and immunogenic-
ity of two doses of FINLAY-FR-2 and a third heterologous dose
of FINLAY-FR-1A in children (3-11 y/o) and teenagers (12-18 y/o).
Two interim analyses would decide interruption/continuation of
the study, depending on serious adverse events (AEs) during phase
I.
Phase I was conceived in a two-step, incorporating firstly 25
children 12-18 y/o (sequence 1). The first interim report (no se-
rious AE detected) 7 days after their vaccination allowed incorpo-
rating 25 children 3-11 y/o (phase I, sequence 2 and starting phase
II in 12-18 y/o [n = 150]) . A second interim report 7 days after se-
quence 2 (no serious AE detected) allowed starting phase II in chil-
dren 3-11 y/o (n = 150). ( Figure 1 ). Detailed information on trial
sites is presented in Supplementary Material I.
Children were recruited at the community level across the pri-
mary health system by medical doctors. They were included fol-
lowing a physical examination, parent interview, and phase I clin-
ical laboratory assays. Key inclusion criteria were weight-height
nutritional assessment, physical examination without alterations,
clinical laboratory results within the range of reference values
(only phase I), and microbiology laboratory tests. Key exclusion cri-
teria were any acute infection, previous or current history of SARS-
CoV-2 infection, and being a contact of a positive COVID-19 case. A
detailed description of selection criteria appears in Supplementary
Material II.
Ethical issues
The trial was approved by the Ethical Committee at the “Juan
Manuel Marquez” Pediatric Hospital and endorsed by the Cuban
National Pediatric Group. The Cuban National Regulatory Agency
(Centre for State Control of Medicines and Medical Devices, Cuban
and National Regulatory Agency) approved the trial (June 10, 2021,
Authorization Reference: 05.010.21BA).
Independent Data Monitoring Committees formed by five exter-
nal members specialized in pediatric clinical practice, immunology,
and statistics were in charge of two interim analyses during phase
I.
The trial was conducted according to the Declaration of
Helsinki, Good Clinical Practice, and the Cuban National Immuniza-
tion Program. During recruitment, the medical investigators pro-
vided to the parents, both orally and written, all information about
the vaccine and its potential risks and benefits. Written informed
consent was obtained from both parents; children ≥over 12 y/o
should assent. The decision to participate was not remunerated.
The National Clinical Trials Coordinating Centre (CENCEC) was
responsible for monitoring the trial in terms of adherence to the
protocol, Good Clinical Practice, and data accuracy.
165
R. Puga-Gómez, Y. Ricardo-Delgado, C. Rojas-Iriarte et al. International Journal of Infectious Diseases 126 (2023) 164– 173
Figure 1. Flow chart: recruitment, inclusion, vaccination and follow-up of 3-18 years old children in phase I/II trial.
AE, adverse event; PCR, polymerase chain reaction.
Trial registry: RPCEC0 0 0 0 0374 (Cuban Public Registry of Clinical
Trials and World Health Organization International Clinical Registry
Trials Platform) ( International register clinical trials, 2021 ).
Products under evaluation
FINLAY-FR-2 (RBD chemically conjugated to the carrier protein
tetanus toxoid) and FINLAY-FR-1A (RBD dimer), adjuvanted in alu-
166
R. Puga-Gómez, Y. Ricardo-Delgado, C. Rojas-Iriarte et al. International Journal of Infectious Diseases 126 (2023) 16 4– 173
mina hydroxide, were produced at the Finlay Vaccine Institute
and the Centre for Molecular Immunology, in Havana, Cuba, under
Good Medical Practice conditions. Both are subunit vaccines-based
SARS-CoV-2 RBD, sequence Arg319-Phe541, produced in genetically
modified Chinese hamster ovary (CHO) cells. Formulations are de-
tailed in Supplementary Material III-Table S1.
Product batches used: FINLAY-FR-2 (E1002S02X, E1002S02);
FINLAY-FR-1A (E1001SP).
Procedures
Reverse transcriptase-polymerase chain reaction (PCR) SARS-
CoV-2 was performed in all participants at least 72 hours before
each dose. Participants with negative PCR results received the vac-
cine by intramuscular injections in the deltoid region. Immuniza-
tion schedule : two doses of FINLAY-FR-2 and a heterologous third
dose of FINLAY-FR-1A 28 days apart (immunization on days 0, 28,
56). After each immunization, participants were on-site evaluated
for 1 hour. Medical control visits were planned at 24, 48, and 72
hours and on days 7, 14, and 28 after each dose. AEs were reg-
istered by parents daily. Serum samples were collected on day 0
(before vaccination) and 14 days after the second and third doses
(days 42 and 70). Peripheral blood mononuclear cells were ob-
tained before vaccination and after the third dose (day 70) in a
participant subset of 45 children randomly selected in each age
subgroup.
Outcomes
Primary outcomes. Phase I: occurrence of serious AEs, measured
daily for days after each dose. Phase II: Percentage of subjects with
seroconversion ≥4-fold increase of immunoglobulin (Ig)G anti-RBD
over pre-immunization, on days 42 and 70.
Secondary outcomes. Phase I and phase II: Solicited local and
systemic AEs, measured during 7 days after each dose; unsolicited
AEs, measured 28 days after each dose; neutralizing antibody titers
(on days 42 and 70, on a sample subset), inhibition of RBD-human
angiotensin I-converting enzyme 2 (hACE2) interaction (on days 42
and 70). Phase II: Occurrence of serious AEs, measured 28 days af-
ter each dose. Outcomes are detailed in Supplementary Material
III).
Outcomes and safety assessments are detailed in Supplemen-
tary Materials IV and V.
Immunogenicity assessment
Immunogenicity was evaluated by: (i) quantitative ultramicro
enzyme-linked immunoassay (ELISA) (UMELISA SARS-CoV-2 anti-
RBD; (ii) competitive ELISA determined the inhibitory capacity
of antibodies for blocking the RBD-hACE2 interaction, expressed
as percentage inhibition and molecular virus neutralization titer
(mVNT
50
); (iii) conventional virus neutralization titer (cVNT
50
) vs
D614G, Alpha, Beta, Delta, and Omicron variants; (iv) RBD-specific
T-cells response producing interferon (IFN)- γand interleukin (IL)-
4. Immunogenicity assessment and techniques are described in
Supplementary Material VI. All immunological evaluations were
performed by external laboratories from the Centre for Immunoas-
says, the Centre of Molecular Immunology, and the National Civil
Defense Research Laboratory. The T-cells response was evaluated at
Finlay Vaccine Institute. A detailed description of immunogenicity
assessments and techniques is described in Supplementary Mate-
rial VI.
Children’s convalescent serum panel
A Cuban children’s convalescent serum panel was made with
sera from 82 patients (3-18 y/owho) who recovered from COVID-
Tabl e 1
Demographic characteristics of subjects included in the clinical trial.
Age groups
3-11 years 12-18 years Tot al 3-18 years
N 175 175 350
Sex
Female 80 (45.7%) 83 (47.4%) 163 (46.6%)
Male 95 (54.3%) 92 (52.6%) 187 (53.4%)
Skin color
White 122 (69.7%) 116 (66.3%) 238 (68.0%)
Black 9 (5.1%) 11 (6.3%) 20 (5.7%)
Multiracial 44 (25.1%) 48 (27.4%) 92 (26.3%)
Age (years)
Mean (SD) 7.4 (2.5) 15.1 (2.1) 11.3 ±4.5
Median (IQR) 8.0 (5.0) 15.0 (4.0) 11.5 ±7.0
Range 3; 11 12;18 3-18
Weight (kg)
Mean (SD) 29.4 (10.1) 54.7 (9.0) 42.0 ±15.9
Median (IQR) 27.5 (14.0) 55.0 (13.0) 43.0 ±27.7
Range 13.0; 58.0 32.0; 80.0 13.0; 80.0
Height (cm)
Mean (SD) 129.1 (17.2) 164.3 (9.6) 146.7 ±22.5
Median (IQR) 131.0 (26.0) 164.0 (13.0) 151.0 ±34.0
Range 92; 172 142; 190 92-190
Body mass index (kg/m
2
)
Mean (SD) 17.0 (2.0) 20.2 (2.3) 18.6 ±2.7
Median (IQR) 16.7 (2.7) 19.9 (3.8) 18.3 ±4.1
Range 13.2; 22.8 14.6; 25.5 13.2-25.5
Data are n (%) unless otherwise specified.
Range presented as minimum; maximum.
Abbreviations: IQR, interquartile range; SD, standard deviation
19. Detailed information about panel composition and immune
characterization is presented in Supplementary Material VII.
Statistical analysis
For phase I, the calculation of sample size was done consider-
ing a 2-sided 95% confidence interval (CI) for one proportion with
a width equal to 0.09 to estimate a serious AE rate of < 1%. For
phase II, a similar method was used to estimate a seroconversion
of around 50%, with a lower bound of the CI > 30% (trial hypoth-
esis) and a dropout of 20%. This resulted in a sample size of 350
subjects (including subjects from phase I). Detailed statistical tools,
procedures, and definitions are presented in Supplementary Mate-
rial VIII.
Results
Figure 1 and Table 1 describe the study design and demo-
graphic characteristics of the participants. From June 11 to July
14, 2021, 426 children (3-18 y/o) were recruited, 350 that accom-
plished the selection criteria were included, and 306 completed
the study. There was a balanced ratio of sex and ethnicity; the
mean age was 11.3 years (SD 4.5).
Phase I started by vaccinating 25 children 12-18 y/o with
FINLAY-FR-2; the first interim analysis was done 7 days after vacci-
nation, indicating the absence of serious AEs. In consequence, the
trial proceeded to phase I sequence 2, incorporating 25 children
aged 3-11 and 150 children aged 12-18 of phase II. The second in-
terim analysis showed no serious AE in children 3-11 y/o (sequence
2); the trial completed phase II, vaccinating 150 children 3-11 y/o
with FINLAY-FR-2 first dose.
During the vaccination scheme, 86 children (53.1%) suffered at
least one AE; the frequency was higher (60%) in teenagers than in
young children (46.3%). Severe and serious vaccine-associated AEs
did not occur ( Table 2 ). Local AE predominated; the most com-
mon was local pain (47.7%), and all others had frequencies < 5%;
only 1.1% reported fever ( Table 3 ). More than 90% of AEs were
167
R. Puga-Gómez, Y. Ricardo-Delgado, C. Rojas-Iriarte et al. International Journal of Infectious Diseases 126 (2023) 16 4– 173
Tabl e 2
General characteristics of AEs.
Age groups
3-11 years 12-18 years Total
N 175 175 350
Subjects with some AE 81 (46.3%) 105 (60.0%) 186 (53.10%)
Subjects with some VAAE 76 (43.4%) 101 (57.7%) 177 (50.6%)
Subjects with some serious AE 0 (0.0%) 1 (0.6%)
a 1 (0.3%)
Subjects with some serious VAAE 0 (0.0%) 0 (0.0%) 0 (0.0%)
Subjects with some severe AE 0 (0.0%) 0 (0.0%) 0 (0.0%)
Subjects with some severe VAAE 0 (0.0%) 0 (0.0%) 0 (0.0%)
Tota l of Adverse Events 141 182 323
VAAE 126 (89.4%) 160 (87.9) 286 (88.5%)
Serious VAAE 0 (0.0%) 0 (0.0%) 0 (0.0%)
Severe VAAE 0 (0.0%) 0 (0.0%) 0 (0.0%)
Data are n (%).
Abbreviations: AE, adverse event; VAAE, vaccine-associated AE.
a Serious AE: Dengue required hospitalization.
Tabl e 3
Frequency of solicited AEs.
Age groups
3-11 years 12-18 years Total
N 175 175 350
Subjects with some AE 81 (46.3%) 105 (60.0%) 186 (53.10%)
Subjects with solicited local AE
Any 74 (42.3%) 98 (56.0%) 172 (49.1%)
Local pain 69 (39.4%) 98 (56.0%) 167 (47.7%)
Swelling 9 (5.1%) 2 (1.1%) 11 (3.1%)
Local warm 4 (2.3%) 0 (0.0%) 4 (1.1%)
Erythema 5 (2.9%) 1 (0.6%) 6 (1.7%)
Induration 5 (2.9%) 1 (0.6%) 6 (1.7%)
Subjects with solicited systemic AE
Any 5 (2.9) 4 (2.3) 9 (2.6)
General discomfort 1 (0.6%) 3 (1.7%) 4 (1.1%)
Fever ( ≥38
◦C) 2 (1.1) 1 (0.6) 3 (0.9)
Low-grade fever ( < 38
◦C) 4 (2.3) 1 (0.6) 5 (1.4)
Data are n (%) unless otherwise specified.
AE, adverse event.
classified as mild and lasted ≤72 hours, and 88.5% were associ-
ated with vaccination ( Table 3 , Supplementary Material IX-Table
S2). AEs were more frequent after the first dose than after the sec-
ond and third doses (Supplementary Material IX-Table S3). Few un-
solicited AEs were recorded (Supplementary Material IX-Table S4).
Hematology and blood chemistry were studied on days 0 (before
the first dose), 7, and 70 (14 days after the third dose). Data were
separately evaluated in two age groups (3-11 y/o, N = 25, and 12-
18 y/o, N = 24, from phase I). No clinically relevant changes were
observed in hematology and blood chemistry analyses.
Before vaccination, 97.1 % of children were negative for anti-
RBD antibodies; median anti-RBD IgG was 1.95 UA/ml (25
th
-75
th
percentile 1.95; 1.95). Two doses of FINLAY-FR-2 induced serocon-
version in 96.2% of participants (95% CI 93.5; 98.0) and satisfied
the trial hypothesis ( > 50% of seroconversion with a lower bound-
ary of the 2-sided 95% CI > 0.3) ( Table 4 ). The global seroconversion
index was 27.8; the median anti-RBD IgG was 57.0 UA/ml (25
th
-
75
th
percentile 29.8; 153.4 (Table S5). By age subgroup, seroconver-
sion was 99.4% (95% CI 96.5; 99.9) in children 3-11 y/o and 93.1%
(95% CI 88.0; 96.5) in 12-18 y/o (Supplementary Material IX-Table
S5). The heterologous third dose with FINLAY-FR-1A increased se-
roconversion to 100% and seroconversion index to 154.5; anti-RBD
IgG titers also increased significantly ( P < 0.005) to 325.7 UA/ml
(25
th
-75
th percentile 141.5; 613.8) ( Table 4 ). Specific antibody re-
sponse was higher than the elicited by natural infection, evaluated
in Cuban children’s convalescent panel (anti-RBD IgG median 11.5;
25
th
-75
th percentile 5.3; 24.2).
The capacity of anti-RBD IgG for blocking RBD-hACE2 interac-
tion after two doses of FINLAY-FR-2 was 67.4 % (25
th
-75
th per-
centile 42.1; 86.9), and the mVNT
50
was 198. 5 (95% CI 168.4;
233.9); both increased significantly ( P < 0.005) after the third dose
to 92.4 % (25
th
-75
th
percentile 88.3; 93.5) and 1261 (95% CI 1105,5;
1438.8) respectively ( Table 4 ). These values were higher among the
younger children (3-11 y/o) after the second dose but were similar
in both age subgroups after the third dose (Supplementary Mate-
rial IX-Table S5). After two and three doses, mVNT50 was higher
than after natural infection.
After two doses of FINLAY-FR-2, the neutralizing titer vs D614G
variant was higher (geometric mean titer [GMT] 26.4; 95% CI 20.2;
34.5) than the children convalescent panel value (GMT 9.2; 95% CI
6.8; 12.5); and the third dose significantly ( P < 0.005) boosted the
response to GMT 158.4 (95% CI 123.0; 204.0) ( Table 4 ). The neutral-
izing titer vs the variants Alpha, Beta, and Delta was evaluated in
48 children; 100% had neutralizing antibodies vs Alpha and Delta,
and 97.9% vs Beta. cVNT
50
GMT was 173 .8 (95% CI 131.7; 229.5) vs
Alpha, 142 (95% CI 101.3; 198.9) vs Delta, and 24.8 (95% CI 16.8;
36.6) vs Beta; (a 2.2-fold decrease for Delta and 7.0-fold decrease
for Beta, compared with D614G). Additionally, a subset of 33 paired
samples was also evaluated vs Omicron variant, showing a neutral-
ization titer of 99.2 (95% CI 67.8; 145.4) ( Table 5 ).
There was a good correlation among all humoral immunological
variables. Predictive cut-off for attaining cVNT
50
over 50 was esti-
mated by receiver operating characteristic (ROC) curve as: 192.2
AU/ml for IgG concentration, 87.1% for the inhibition of RBD:hACE2
and 427 for mVNT
50
(Supplementary Material X-Table S6, Figure
S1).
RBD-specific T-cell response in a subset of 45 participants fully
vaccinated was determined by measuring IFN- γand IL-4 expres-
sion in peripheral blood mononuclear cells. The number of IFN-
γand IL-4 secreting cells was statistically higher ( P < 0.001) than
their baseline levels ( Figure 2 ).
The safety and immune response in children were compared
with young adults (aged 19-39 y/o) vaccinated in phase I and
phase II studies with the same vaccine regimen, as recommended
by the FDA (2021). Safety profile was similar in both (Supplemen-
tary Material X-Tables S7, S8, Figure S2). An immunobridging analy-
sis was performed for anti-RBD IgG, mVNT
50
, and cVNT
50
between
children and young adults. IgG elicited after two doses of FINLAY-
FR-2 was 57.0 UA/ml (25
th
-75
th percentile 29.8; 153.4), while for
young adults, it was 46.4 (25
th
-75
th percentile 17.4 ; 108.8); af-
ter the heterologous third dose of FINLAY-FR-1A these values in-
creased to 325.7 (25
th
-75
th percentile 141.5; 613.8) in children and
228.0 (25
th
-75
th percentile 95.8; 394.3) in young adults. mVNT
50
was 198. 5 (95% CI 168.4; 233.9) in children after the second dose
168
R. Puga-Gómez, Y. Ricardo-Delgado, C. Rojas-Iriarte et al. International Journal of Infectious Diseases 126 (2023) 16 4– 173
Tabl e 4
Humoral immune response induced after two doses of FINLAY-FR-2 and the third heterologous dose with FINLAY-FR-1A.
Age group 3-18 y/o Cuban children’s convalescent serum panel
Post-2
nd
dose Post-3
rd
dose
N 318 306 82
Anti-RBD IgG
seroconversion rate
N (%) 305/317 (96.2) 305/305 (100.0)
a ND
95% CI 93.5; 98.0 99.8; 100.0
Anti-RBD IgG AU/ml Median 57.0 325.7
a 11.5
25
th
-75
th 29.8; 153.4 141.5; 613.8 5.3; 24.2
Seroconversion index Median 27.8 154.5
a ND
25
th
-75
th 14.3; 69.0 67.2; 260.9
RBD:hACE2 Inh% Median 67.4 92.4
a 20.8
25
th
-75
th 42.1; 86.9 88.3; 93.5 10.9; 40.8
mVNT
50 GMT 198.5 1261.2
a 35.2
95% CI 168.4; 233.9 1105.5; 1438.8 25.3; 48.9
cVNT
50
vs D614G N 123 131 70
GMT 26.4 158.4
a 9.2
95% CI 20.2; 34.5 123.0; 204.0 6.8; 12.5
Abbreviations: Anti-RBD IgG seroconversion rate, % of subjects with seroconversion (95% CI); AU/ml, anti-RBD IgG concentration ex-
pressed in arbitrary units/ml; CI, confidence interval; cVNT
50
: conventional live-virus neutralization titer; GMT, geometric mean titer;
Ig, immunoglobulin; mVNT
50
: molecular virus neutralization titer; ND, not determined; RBD, receptor binding domain; RBD:hACE2
Inh%: RBD:hACE2 inhibition % at a serum dilution 1/100; Seroconversion index: fold increase of IgG concentration respect to baseline
(median; 25
th
-75
th
percentile).
Footnote: t
0
or baseline anti-RBD IgG was 1. 95 (25
th
-75
th
percentile: 1.95; 1.95).
a P < 0.005 vs post-2
nd dose McNemar test (anti-RBD IgG seroconversion %), Wilcoxon Signed Ranks test (anti-RBD IgG AU/ml,
RBD:hACE2 Inh%) or paired Student’s t -test (mVNT
50
, cVNT
50
, log-transformed).
Tabl e 5
Conventional live-virus neutralization titers against SARS-CoV-2 variants Alpha, Delta, Beta and Omicron.
D614G Alpha Delta Beta Omicron BA.1
cVNT
50 N 48 48 48 48
GMT 173.8 142.0 76.8
a 24.8
a
95% CI 131.7; 229.5 101.3; 198.9 54.8; 107.7 16.8; 36.6
cVNT
50 N 33 33 33 33 33
GMT 169.8 126.6
a 72.4
a 19.4
a 99.2
a
95% CI 120.2; 239.7 86.7; 184.8 47.4; 110.6 12.7; 29.7 67.8; 145.4
Abbreviations: CI, confidence interval; cVNT
50
: conventional live-virus neutralization titer; GMT, geometric
mean titer.
Sera from 48 children vaccinated with complete schedule (two doses FINLAY-FR-2 + one dose FINLAY-FR-1A,
28 days apart) were evaluated against D614G, Alpha, Delta and Beta variants. Of them, 33 paired samples
were evaluated also vs Omicron.
a P < 0.005 paired Student’s t -test (cVNT
50
, log-transformed) respect to D614G variant.
and 1261.2 (95% CI 1105.5; 1438.8) after the third; in young adults
were 94.9 (95% CI 75.0; 120.2) and 503.7 (95% CI 432.6; 586.6) af-
ter two and three doses ( Figure 3 ). We found significant differences
( P < 0.05) for IgG and mVNT
50
between 3-18 y/o children and 19-
39 y/o young adults; higher values were obtained in children after
both the second and the third dose. Viral neutralization titers after
the second dose were measured at different time points in chil-
dren and young adults (on day 42 in children and day 56 in young
adults), making their comparison only approximate.
The non-inferiority analysis was performed with cVNT
50
data,
following the FDA’s (2021) recommendation. After three doses (on
day 70), cVNT
50
in children was 158.4 (95% CI 123.0; 204.0) and
122.8 (80.2; 188.0) for young adults (n = 43, data available) ( Figure
3 ). The immune response in 3-18 y/o, as well as in age subgroups
3-11 y/o and 12-18 y/o, was non-inferior to that observed in 19-
39 y/o young adults. The cVNT
50
GMT ratio 14 days after the third
dose was 1.25 (95% CI 0.77; 2.02) ( Table 6 ) for children 3-18 y/o,
respectively, to adults, which met the non-inferiority criterion (i.e.,
a lower boundary of the two-sided 95% CI of > 0.67). In addi-
tion, both age subgroups (3-11 y/o and 12-18 y/o) met the non-
inferiority criterion.
Based on immunogenicity data of vaccinated children and
the immune response to natural infection (children convalescent
panel), a prediction of clinical efficacy was estimated through a
linear regression model. By using cVNT
50
as the predictive vari-
able, the estimated efficacy vs D614G is 91.3% (95% CI 84.6; 95.1)
after two doses and 97.4 % (95% CI 91.5; 99.2) after three doses
( Figure 4 ).
Discussion
This study describes, for the first time, the safety and immuno-
genicity in children 3-18 y/o of two doses of FINLAY-FR-2, fol-
lowed by a third heterologous dose of FINLAY-FR-1A. The frequency
of local and systemic AE was 49.0% and 2.6%, respectively, lower
than after messenger RNA (mRNA) COVID-19 vaccination. After two
doses, BNT162b2 reported 86.0% and 66.0 of children 12-15 y/o
with local and systemic AEs, while mRNA-1273 reported 94.2% and
68.3% (aged 12-17 y/o), respectively. In our study, local pain was
reported by 51.4% of children aged 12-18 y/o after the first dose,
17% after the second, and 17. 3% after the third dose. BNT162b2
and mRNA-1273 vaccines in adolescents reported 86.0% and 94.2%
with local pain after the first dose; and 79.0% and 92.4% after the
second, respectively. FINLAY-FR-2 and FINLAY-FR-1A caused general
discomfort (the most frequent systemic AE) only in 1.7 % of children
12-18 y/o, while mRNA vaccines provoked fatigue, headache, chills,
muscle pain, or fever in 10-68.5% of adolescents ( Ali et al., 2021 ;
Frenck et al., 2021 ). In children 3-11 y/o, local pain was the unique
AE with frequency > 10% during this study; children 5-11y/o vacci-
nated with BNT162b2 reported local pain (74.0%), redness (19.0%),
swelling (15.0%), fatigue (39.0%), and headache (28.0%) (Walter et
al., 2021). Myocarditis and pericarditis have been reported in ado-
169
R. Puga-Gómez, Y. Ricardo-Delgado, C. Rojas-Iriarte et al. International Journal of Infectious Diseases 126 (2023) 164– 173
Figure 2. IFN- γ- and interleukin-4-secreting cells in peripheral blood mononuclear cells stimulated with receptor binding domain. Children 3-11 (N = 24) and 12-18 years
old (N = 21) received two doses (on days 0, 28) of FINLAY-FR-2 and a heterologous third dose (on day 56) of FINLAY-FR-1A. P -value represents the statistic differences as
indicated.
IFN, interferon; PBMC, peripheral blood mononuclear cells.
Figure 3. Immunobridging comparison of humoral immune response elicited in children (3-18 y/o) respect to young adults (19-39 y/o from phase I and II clinical trials)
after two doses of FINLAY-FR-2 (day 42) and the third dose of FINLAY-FR-1A (day 70). (a) anti-RBD IgG median (25
th
-75
th
percentile); (b) mVNT
50
GMT (95% CI); (c) cVNT
50
GMT (95% CI). Bleeding was on day 42 and 70 (14 days after the second and third dose), except for cVNT50 adults after the second dose was on day 56. Mann-Whitney U
test (anti-RBD IgG AU/ml) or Student’s t -test (mVNT
50
, cVNT
50
, log-transformed). P -value represents the statistic differences as indicated.
cVNT
50
, conventional live-virus neutralization titer; GMT, geometric mean titer; Ig, immunoglobulin; mVNT
50
, molecular virus neutralization titer; RBD, receptor binding
domain; y/o, years old.
170
R. Puga-Gómez, Y. Ricardo-Delgado, C. Rojas-Iriarte et al. International Journal of Infectious Diseases 126 (2023) 16 4– 173
Tabl e 6
Immunobridging of cVNT
50
in children and young adults after heterologous scheme (two doses of FINLAY-FR-2
and the third heterologous dose of FINLAY-FR-1A)
Age group No. of participants
cVNT
50
GMT (95% CI)
Geometric mean ratio
(95% CI) vs 19 to 39 y/o
19-39 y/o 43 127.0 (89.6; 179.80) –
3-18 y/o 131 158.4 (123.0; 204.0) 1.25 (0.77; 2.02)
3-11 y/o 66 181.6 (120.6; 273.3) 1.43 (0.80; 2.54)
12-18 y/o 65 137.9 (101.8; 186.9) 1.08 (0.68; 1.73)
Abbreviations: CI, confidence interval; cVNT
50
: conventional live-virus neutralization titer; GMT, geometric
mean titer; y/o, years old.
GMT and two-sided 95% CIs were calculated by exponentiating the mean logarithm of the titers and the cor-
responding CIs (based on the Student’s t -distribution). The geometric mean ratio and two-sided 95% CIs were
calculated by exponentiating
the mean difference of the logarithms of the titers (in children/adolescents co-
horts minus the 19-39-y/o cohort) and the corresponding CIs (based on the Student’s t -distribution). The non-
inferiority criterion was met, since the lower boundary of the two-sided CI for the geometric mean ratio was
greater than 0.67.
Figure 4. Prediction of clinical efficacy in children from the correlation between antibody responses and efficacy rate. Panels display correlation of cVNT
50
neutralization and
ratios, respectively for seven vaccines in adults; two doses of FINLAY-FR-2 (represented as SOBERANA 02) and the heterologous three doses adding FINLAY-FR-1A (represented
as SOBERANA Plus) in children. The y-axis is estimated log risk ratio reported on the vaccine efficacy scale. The x-axis is log ratio of the
peak geometric mean neutralization
at 7-28 days post-vaccination, relative to human or children convalescent sera.
CI, confidence interval; cVNT
50
: conventional live-virus neutralization titer; GMT, geometric mean titer.
lescents after mRNA COVID-19 vaccination ( Marshall et al., 2021 ;
Oster et al., 2022 ); these AEs were not observed here.
The comparison of the humoral immune response elicited by
vaccination to the response elicited by natural infection has been
a useful tool for the development of several anti-SARS-CoV-2 vac-
cines ( Keech et al., 2020 ; Yang et al., 2021 ). Two shots of FINLAY-
FR-2 every 28 days in children induced a robust humoral response,
with higher levels of antibodies and a similar neutralizing capac-
ity of the response elicited by natural infection. The third dose of
FINLAY-FR-1A boosted both the production of antibodies and their
neutralizing capacity, surpassing the immune response in convales-
cent children, as had been previously observed in clinical trials in
adults ( Eugenia-Toledo-Romaní et al., 2022a , 2022b ).
The induction of specific T-cell response is critical for the pro-
tection of viral infections. The heterologous three-dose schedule
in children developed a balanced activation of IFN- γand IL-4-
secreting cells from peripheral blood mononuclear cells (PBMC),
indicating a mixed Th1/Th2 response, as reported in adults af-
ter the same vaccination scheme ( Eugenia-Toledo-Romaní et al.,
2022a ).
The SARS-CoV-2 variants of concern Alpha, Beta, Delta, and re-
cently Omicron, have modified the pandemic landscape worldwide
( Fontanet et al., 2021 ). Here, we report the capacity of anti-RBD
antibodies for neutralizing Alpha, Beta, Delta, and Omicron vari-
ants, with a fold-reduction of 2.2 for Delta and 7.0 for Beta com-
pared with D614G, as we found in adults ( Eugenia-Toledo-Romani
et al., 2022b ). In an independent study from the “Pedro Kourí”
Tropical Medicine Institute in Havana, sera from 20 adults (vac-
cinated with the same vaccine regimen) neutralized the Omicron
variant ( Carles, 2022 ; Portal-Miranda, 2022 ).
We conducted this clinical trial during the Delta wave, the
worst period of the Cuban epidemic ( Rodriguez, 2021 ); in such
a context and due to ethical reasons, a placebo-controlled clini-
cal trial was not ethical, and this is the main limitation of the
171
R. Puga-Gómez, Y. Ricardo-Delgado, C. Rojas-Iriarte et al. International Journal of Infectious Diseases 126 (2023) 164– 173
study. Lacking a control group, two analytical tools complemented
the study: immunobridging with the immune response in young
adults previously vaccinated during clinical trials with the same
vaccination schedule (no concurrent reference population) as rec-
ommended by the FDA (2021); and prediction of clinical efficacy
based on immunological response ( Khoury et al., 2021 ; Kristen et
al., 2021). First, we found a non-inferior response for the GMT ratio
of SARS-CoV-2 cVNT
50
after the three-dose scheme in participants
3-11 and 12-18 y/o relative to a 19-39 y/o reference population
(no concurrent). The comparison met the non-inferiority criterion
with a ratio of 1. 43 (95% CI 0.8-2.54) for 3-11 y/o and 1. 08 (95%
CI 0.68-1.73) for 12-18 y/o, satisfying the FDA (2021) recommenda-
tions (a lower boundary of the 2-sided 95% CI of > 0.67). Similar
analyses have been reported by BNT162b2 and mRNA-1273 vac-
cines using 19-25 y/o as reference population ( Walter et al., 2022 ;
Ali et al., 2021 ). Based on published results, we considered young
adults as immunocompetent for up to 39 years ( Lopez-Sejas et al.,
2016 ; Thapa and Farber, 2019 ; Ventura et al., 2017 ); this increased
the number of cVNT
50
data for comparison in the reference popu-
lation.
Second, a prediction of clinical efficacy based on immunologi-
cal response has been advanced for other vaccines ( Khoury et al.,
2021 ; Kristen et al., 2021). Using this model, for adults aged 19-
80 y/o, we anticipated a clinical efficacy between 58% and 87% af-
ter the first two doses and between 81% and 93% after the three-
dose scheme vs the D614G variant ( Eugenia-Toledo-Romani et al.,
2022b ). These results were confirmed during a phase III clini-
cal trial reporting a 69.7% efficacy for the two-dose schedule of
FINLAY-FR-2 and 92.0 % for the heterologous three-dose sched-
ule during the Beta period (Eugenia-Toledo-Romani et al., 2021).
Here, the model predicts 91.3% clinical efficacy after two doses of
FINLAY-FR-2 and 97.4% after the third dose of FINLAY-FR-1A in chil-
dren vs the D614G strain.
Starting vaccination of children at 2 y/o is key for controlling
the pandemic, reducing transmission, and reducing the emergence
of new variant of concerns ( Petersen and Buchy, 2021 ). The safety
and immunological results reported here supported the emergency
use authorization of FINLAY-FR-2 and FINLAY-FR-1A as a heterolo-
gous scheme for children 2-18 y/o. A massive immunization cam-
paign started on September 5, 2021, fully vaccinating 1.8 million
Cuban children (96% of the 2-18 y/o Cuban population [ Augustin,
2022 ; Reed, 2022 ]). These results support public health vaccina-
tion strategies, providing children as young as 2 years with a safe
and effective vaccine scheme to prevent COVID-19.
Authors contributions statment
D.G.R, Y.V.B, R.P.G, and V.V.B conceptualized the study. R.P.G,
Y.R.D, C.R.I, L.C.H. M.P.B, D.V.M, N.P.P, J.C.F.P, M.S.M, M.E.T.R were
clinical investigators. B.P.M, M.R.G, Y.C.E supervised the trial. B.S.R,
L.R.N, R.P.N, T.H.G, T.F.B, M.D.E, J.M.E.P, Y.I.H, I.C.Q, S.F.C, Y.C.R,
D.S.M, A.P.D, E.G.O were responsible of immunological evaluations.
R.G.M performe the data curation. C.V.S performed statistical anal-
ysis. D.G.R, C.V.S, Y.G.V, Y.V.B and V.V.B wrote the manuscript. The
members of SOBERANA Research Group participated in different
processes during the trial: data colection, supervision, quiality as-
surance, coordination among others.
Declaration of competing interest
The authors RPG, YRD, CRI, LCH, MPB, DVM, NPP, CVS, APD,
EGO, YCE, JCFP, MSM, MDE, JMEP, YIH, and METR declare that they
have no known competing financial interests or personal relation-
ships that could have appeared to influence the work reported in
this paper.
The authors BPM, MRG, BSR, LMRN, RPN, RGM, THG, TFB, ICQ,
SFC, YCR, DSM, YGV, YVB, DGR, and VVB work at Finlay Vaccine
Institute or the Centre of Molecular Immunology, institutions that
develop and manufacture the vaccine candidates but have not re-
ceived an honorarium for this paper.
BSR, SFC, YCR, LRN, DSM, YVB, DGR, and VVB have filed patent
applications related to the vaccine FINLAY-FR-2.
DD and AB work at Pasteur Institute of Iran and are co-
developer of the vaccines.
Funding
This work was supported by the Finlay Vaccine Institute,
BioCubaFarma, and the National Funds for Sciences and Technol-
ogy from the Ministry of Science, Technology, and Environment
(FONCI-CITMA-Cuba, contract 2020-20).
Acknowledgments
We especially thank all the parents and children for participat-
ing in the clinical trial. We recognize the contribution of all the
medical and nurse staff at clinical sites. We thank Dr. Lila Castel-
lanos for scientific advice.
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi: 10.1016/j.ijid.2022.11.016 .
References
Augustin Ed. Cuba leads the world in vaccinating children as young as two
against Covid. The Guardian. https://www.theguardian.com/world/2022/feb/01/
cuba- leads- world- vaccinating- children
, February 1, 2022 (accessed 17 February,
2022).
Ali K, Berman G, Zhou H, Deng W, Faughnan V, Coronado-Voges M, et al.
Evaluation of mRNA-1273 SARS-CoV-2 vaccine in adolescents. N Engl J Med
2021;385:2241–51
.
Carles Zerquera JM. Rapid Respose: Cuban’s vaccines against Omicron. BMJ
2022;376:o66
.
Cuban and National Regulatory Agency. Authorization for emergency use of SOBER-
ANA02 in adults, Resolution 2021 (144/2021); 2021 https://www.cecmed.cu
(ac-
cessed 17 November 2022)
.
Dal-Ré R, Caplan AL. Current COVID-19 vaccine trials in high-income countries: are
placebo-controlled trials ethical? Clin Microbiol Infect 2021;27:1565–7
.
Delahoy MJ, Ujamaa D, Whitaker M, O’Halloran A, Anglin O, Burns E, et al.
Hospitalizations associated with COVID-19 among children and adolescents -
COVID-NET, 14 states, March 1, 2020-August 14, 2021. MMWR Morb Mortal
Wkly Rep 2021;70:1255–60
.
Elliott P, Bodinier B, Eales O, Wang H, Haw D, Elliott J, et al. Rapid increase in
Omicron infections in England during December 2021: REACT-1 study. Science
2022;375:1406–11
.
Eugenia-Toledo-Romaní ME, Verdecia-Sánchez L, Rodriguez-González M, Rodríguez-
Noda L, Valenzuela-Silva C, Paredes-Moreno B, et al. Safety and immunogenic-
ity of anti-SARS CoV-2 vaccine SOBERANA 02 in homologous or heterologous
scheme: open label phase I and phase IIa clinical trials. Vaccine 2022a;40:4220–
30. doi:
10.1016/j.vaccine.2022.05.082 .
Eugenia-Toledo-Romani ME, García-Carmenate M, Verdecia-Sánchez L, Pérez-
Rodríguez S, Rodriguez-González M, Valenzuela-Silva C, et al. Safety and im-
munogenicity of anti-SARS-CoV-2 heterologous scheme with SOBERANA 02
and SOBERANA Plus vaccines: phase IIb clinical trial in adults. Med 2022b;3.
doi:
10.1016/j.medj.2022.08.001 .
Fontanet A, Autran B, Lina B, Kieny MP, Karim SSA, Sridhar D. SARS-CoV-2 variants
and ending the COVID-19 pandemic. Lancet 2021;397:952–4
.
Frenck RW, Klein NP, Kitchin N, Gurtman A, Absalon J, Lockhart S, et al. Safety,
immunogenicity, and efficacy of the BNT162b2 Covid-19 vaccine in adolescents.
N Engl J Med 2021;385:239–50
.
Han B, Song Y, Li C, Yan g W, Ma Q, Jiang Z, et al. Safety, tolerability, and immuno-
genicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy children
and adolescents: a double-blind, randomised, controlled, phase 1/2 clinical trial.
Lancet Infect Dis 2021;21:1645–53 .
Huang YL, Wu CY. Carbohydrate-based vaccines: challenges and opportunities. Ex-
pert Rev Vaccines 2010;9:1257–74
.
International register clinical trials. Identifier RPCEC0 0 0 0 0374. Phase I–II study, se-
quential during phase I, open-label, adaptive and multicenter to evaluate the
safety, reactogenicity and immunogenicity of a heterologous two-dose sched-
ule of the prophylactic anti-SARS- CoV-2 vaccine candidate, FINLAY-FR- 2 and
172
R. Puga-Gómez, Y. Ricardo-Delgado, C. Rojas-Iriarte et al. International Journal of Infectious Diseases 126 (2023) 164– 173
a dose of FINLAY-FR-1A. https://rpcec.sld.cu/en/trials/RPCEC0 0 0 0 0374-En , 2021
(accessed 1 December 2021).
Keech C, Albert G, Cho I, Robertson A, Reed P, Neal S, et al. Phase 1–2 trial of
a SARS-CoV-2 recombinant spike protein nanoparticle vaccine. N Engl J Med
2020;383:2320–32
.
Khoury DS, Cromer D, Reynaldi A, Schlub TE, Wheatley AK, Juno JA. Neutralizing
antibody levels are highly predictive of immune protection from symptomatic
SARS-CoV-2 infection. Nat Med 2021;27:1205–11
.
Lopez-Sejas N, Campos C, Hassouneh F, Sanchez-Correa B, Tarazon a R, Pera A,
Solana R. Effect of CMV and aging on the differential expression of CD300a,
CD161, T-bet , and Eomes on NK cell subsets. Front Immunol 2016;7:476
.
Marshall M, Ferguson ID, Lewis P, Jaggi P, Gagliardo C, Collins JS, Shaughnessy R,
Caron R, Fuss C, Corbin KJE, Emuren L, Faherty E, Hall EK, Di Pentima C, Os-
ter ME, Paintsil E, Siddiqui S, Timchak DM, Guzman-Cottrill JA. Symptomatic
acute myocarditis in 7 adolescents after Pfizer-BioNTech COVID-19 vaccination.
Pediatrics 2021;148 .
Oster ME, Shay DK, Su JR, Gee J, Creech CB, Broder KR, et al. Myocarditis cases re-
ported after mRNA-Based COVID-19 vaccination in the US from December 2020
to August 2021. JAMA 2022;327:331–40
.
Petersen E, Buchy P. Vaccination against SARS-CoV-2 should be included in child-
hood vaccination programs. Int J Infect Dis 2021;106:429–30
.
Portal-Miranda JA. Las vacunas cubanas generan anticuerpos ante ómicron: ese éx-
ito no puede llevarnos a la confianza. http://www.cubadebate.cu/opinion/2022/
01/26/2022 , 2022 (accessed 26 January 2022).
Reed G. Cuban COVID-19 vaccines for children: Rinaldo Puga MD MS Principal In-
vestigator, Pediatric Clinical Trials for Soberana 02 and Soberana Plus. MEDICC
Rev 2022;24:14–18
.
Rodriguez A. Virus slams Cuba as it races to roll out its new vaccines. ABC
News 2021 https://abcnews.go.com/Health/wireStory/virus- slams- cuba- races-
roll- vaccines- 78953663
. (accessed 17 February 2022) .
Thapa P, Farber DL. The role of the thymus in the immune response. Thorac Surg
Clin 2019;29:123–31
.
Valdes-Balbin Y, Santana-Mederos D, Paquet F, Fernandez S, Climent Y, Chiodo F,
et al. Molecular aspects concerning the use of the SARS-CoV-2 receptor binding
domain as a target for preventive vaccines. ACS Cent Sci 2021a;7:757–67
.
Valdes-Balbin Y, Santana-Mederos D, Quintero L, Fernández S, Rodriguez L,
Sanchez Ramirez B, et al. SARS-CoV-2 RBD-tetanus toxoid conjugate vaccine
induces a strong neutralizing immunity in preclinical studies. ACS Chem Biol
2021b;16:1223–33
.
Ventura MT, Casciaro M, Gangemi S, Buquicchio R. Immunosenescence in aging: be-
tween immune cells depletion and cytokines up–regulation. Clin Mol Allergy
2017;15:21
.
Verez-Bencomo V, Fernández-Santana V, Hardy E, Toledo ME, Rodríguez MC, Heyn-
ngnezz L. A synthetic conjugate polysaccharide vaccine against Haemophilus in-
fluenzae type b. Science 2004;305:522–5
.
Wallace M, Woodworth KR, Gargano JW, Scobie HM, Blain AE, Moulia D, et al. The
Advisory Committee on Immunization Practices’ interim recommendation for
use of Pfizer-BioNTech COVID-19 vaccine in adolescents aged 12–15 years-U-
nited States, May 2021. MMWR Morb Mortal Wkly Rep 2021;70:749–52
.
Walter EB, Talaat KR, Sabharwal C, Gurtman A, Lockhart S, Paulsen GC, et al. Evalu-
ation of the BNT162b2 Covid-19 vaccine in children 5 to 11 years of age. N Engl
J Med 2022;386:35–46
.
US Food and Drug Administration. Vaccines and related biological products ad-
visory committee meeting announcement. Licensure and emergency use
authorization of vaccines to prevent COVID-19 for use in pediatric popula-
tions. https://www.fda.gov/advisory-committees/advisory- committee- calendar/
vaccines- and- related- biological- products- advisory- committee- june- 10- 2021-
meeting-announcement
, 2021 (accessed 14 September 2021).
World Health Organization. COVID-19 –landscape of novel coronavirus can-
didate vaccine development worldwide. https://www.who.int/publications/m/
item/draft- landscape- of- covid- 19- candidate- vaccines
, 2021 (accessed 29 De-
cember 2021).
Xia S, Zhang YT, Wang Y, Wang H, Yan g Y, Gao GF, et al. Safety and immunogenic-
ity of an inactivated COVID-19 vaccine, BBIBP-CorV, in people younger than 18
years: a randomised, double-blind, controlled, phase 1/2 trial. Lancet Infect Dis
2022;22:196–208
.
Yang S, Li Y, Dai L, Wang J, He P, Li C, et al. Safety and immunogenicity of a re-
combinant tandem-repeat dimeric RBD-based protein subunit vaccine (ZF2001)
against COVID-19 in adults: two randomised, double-blind, placebo-controlled,
phase 1 and 2 trials. Lancet Infect Dis 2021;21:1107–19
.
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