1. PROPOSAL SUMMARY
Vaccine Breakthrough infection occurs when someone is infected with an organism they are fully
vaccinated against. For SARS-COV-2 vaccine, the test is positive within two weeks of receiving the
entire series of the authorized SARS-COV-2 vaccine (1).
Researchers are assessing the risk factors for COVID-19 in Sudan. The study will be carried out in Sudan,
a country with a population around 40 million that has been hit by COVID-19 pandemic since the
beginning of the year 2020 causing around 88 thousands cases with 3772 deaths until December 2021
according to the
Sudan Federal Ministry of Health. The status of vaccine coverage less than 5% according to Expanded
Program of Immunization – Federal Ministry of Health.
The federal ministry of health's surveillance department receives COVID-19 test results from Sudan's
National Public Health Laboratory and other laboratories. The vaccine was administered to Sudan in
April, due to which 60179 COVID-19 tests were conducted between April 2021 and August 2022, 31693
of which were positive, and 1241 of which were breakthrough cases.
Breakthrough infections after SARS-CoV-2 vaccination have been reported and the number of cases is
increasing (5), (6). Researchers are tracking vaccine breakthrough cases in Khartoum-Sudan in order to
identify the risk factors and their association with other demographic and socioeconomic
characteristics. Currently, the Federal Ministry of Health's emergency operation center has recommended
that a study be conducted by the department of surveillance to provide a clue to the extent breakthrough
infection of COVID-19 infection in Sudan. No studies have been done in the ministry of health, and the
results are urgently needed.
A case-control study will be conducted to determine the risk factors for COVID-19 breakthrough
infection in Sudan in 2022. Specific Objectives are to assess the exposure odds of cases and controls
vaccinated against COVID-19, to determine the risk of COVID-19 following vaccination Based on type,
number, and duration of vaccination and to identify socio-demographic and comorbidity characteristics of
the case and control groups.
Line-list of people who were investigated by National Public Health Laboratory and other laboratories
during the months of April 2021 to August 2022 and who were vaccinated and tested positive or negative
1
using COVID-19 test. Vaccinated individuals who test positive are cases; vaccinated individuals who test
negative are controls.
The sample size was calculated using the Open Epi calculator) and found to be 108 for cases and 215 for
control according to Kelsey et al. To cater about the non-response rate, 20% will be added to cases and to
control. The final sample will be: 130 for cases and 258 for control. The cases and controls will be
selected by simple random sampling using a random number generator. Both cases and controls will be
extracted from the line-list using an extraction form. A pre-coded and pre-tested questionnaire will be
used to collect additional information through phone interviews with cases and controls. A statistician
will code and analyze the data using SPSS version 26. The descriptive data will be presented as graphs or
tables. By estimating crude and adjusted Odd Ratio (OR), the researcher will analyze data using
univariate and multiple logistic regression.
2
The SARS-CoV-2 vaccine has been shown to be highly effective and safe in clinical trials as well as in
clinical settings. 7-13The occurrence of a breakthrough infection, defined as an individual infected with
COVID-19 after receiving all-the-doses of an SARS-CoV-2 vaccine with a 14-day lag, is rare among the
general population.11,12,14 Approximately 183 million persons had received full vaccination by September
27, 2021 in the US. 15,16However, 22 115 cases of breakthrough infection were reported to the CDC. Due to
the absence of symptoms or the mild nature of the disease in most breakthrough cases, 9surveillance data
likely underreport underreported cases.
According to a recent study, individuals with immune dysfunction, including those with HIV or receiving
immunosuppressive medications (such as recipients of solid organ transplant [SOT]), are at a higher risk of
severe COVID-19 outcomes.17 An evaluation of the effectiveness of the SARS-CoV-2 vaccine on
individuals with weakened immune systems has not been conducted in a large-scale clinical setting. Among
HIV-infected persons, marked immunodeficiency, defined by low CD4 count, may indicate antibody
responses to vaccines. 18,19Immunosuppressant medications (such as calcineurin inhibitors or mycophenolic
acid) that are commonly used for the prevention of allograft rejection among SOT recipients can affect
immunity to vaccination. 20,21 In addition, some treatment regimens for autoimmune diseases (eg,
monoclonal antibody therapies, corticosteroids, methotrexate) may interfere with vaccine immunogenicity
and immune response development. The immune response to vaccination is poor in people with cancer,
especially those undergoing bone marrow transplantation and suffering from T-cell deficiency as a
result.22,23
Due to a largely exclusion from clinical trials of SARS-CoV-2 vaccine, there is a large evidence gap for
patients with immune dysfunction. 8.9 The SARS-CoV-2 vaccine demonstrated weakened immune
responses in immunocompromised patients.24-29 Immune dysfunction was associated with lower immune
responses in some groups of individuals assessed by antibody titers as proxies for post vaccine
immunogenicity.24 SARS-CoV-2 vaccines are not yet proven to be effective in real-world settings based on
these proxies of immunogenicity. Accordingly, researchers conducted this study to determine whether
patients with or without immune dysfunction who received SARS-CoV-2 vaccination were more likely to
develop COVID-19 breakthrough infection. The cohort study revealed that full vaccination reduced the risk
of COVID-19 breakthrough infection, regardless of the patient's immune status. People with immune
dysfunction were significantly more likely than those without such a condition to have a COVID-19
breakthrough infection despite full vaccination. It is recommended that vaccination with alternative
strategies be given to people with immune dysfunctions despite having already received a full vaccination
3
(e.g., wearing a mask).30
In a study published in New England Journal of Medicine on Covid-19 breakthrough infections among
vaccinated health care workers, 1497 (13.1%) RT-PCR tests were performed among 11,453 fully
vaccinated health care workers. There were 39 breakthrough cases detected among the workers tested. 18
(46%) of the 39 breakthrough case patients worked as nurses, 10 (26%) as administrative or maintenance
employees, 6 (15%) as allied health professionals, and 5 (13) as physicians. Among the 39 infected
workers, 42 percent were women, and the average age was 42 years old. During the period between the
second vaccine dose and SARS-CoV-2 detection, 39 days were the median (range, 11 to 102 days). An
immunosuppressed individual (3% of infected individuals) was the only one.31
3. OBJECTIVES
3.1 General Objective
To study the risk factors for COVID-19 breakthrough infection in Sudan in 2022.
3.2 Specific Objective
1.
To assess the exposure odds of cases/ controls who were COVID-19 vaccinated
2.
To determine the risk of COVID-19 following vaccination based on the type, number, and duration
ofvaccination.
3.
To identify the socio-demographic and comorbidity characteristics of the control group and the case
group
4
4. METHODOLOGY
4.1 Study design
Observational Analytical Case-control study.
4.2 Study setting / data sources
The study will be carried out in Sudan, a country with a population around 40 million that has been hit by
COVID-19 pandemic since the beginning of the year 2020 causing around 88 thousands cases with 3772
deaths until December 2021 according to the Sudan Federal Ministry of Health. The status of vaccine
coverage less than 5% according to Expanded Program of Immunization – Federal Ministry of Health.
4.3 Study population
5
Line-list of people who were investigated by National Public Health Laboratory and other laboratories
during the months of April 2021 to August 2022 and who were vaccinated and tested positive or negative
using COVID-19 test.
● Cases are persons who are vaccinated and tested positive.
● Controls are persons who are vaccinated and tested negative
4.4 Sampling method
4.4.1 Sample size
Sampling and Sample size:
The
sample
size
was
calculated
using
the
Open
Epi
calculator
(https://www.openepi.com/Menu/OE_Menu.htm) and found to be 108 for cases and 215 for control
according to Kelsey et al. (attached the screen shot). To cater about the non-response rate, 20% will be
added to cases and to control. The final sample will be: 130 for cases and 258 for control.
The sample size calculation using Open Epi Calculator.
Kelsey et al., Methods in Observational Epidemiology 2nd Edition, Table
12-15
Fleiss, Statistical Methods for Rates and Proportions, formulas 3.18 &3.19
6
CC = continuity correction
Results are rounded up to the nearest integer.
Print from the browser menu or select, copy, and paste to other programs.
Results from OpenEpi, Version 3, open source calculator--SSCC
4.4.2 Sampling Technique
The federal ministry of health's surveillance department receives COVID-19 test results from Sudan's
National Public Health Laboratory and other laboratories. The vaccine was administered to Sudan in April,
due to which 60179 COVID-19 tests were conducted between April 2021 and August 2022, 31693 of
which were positive, and 1241 of which were breakthrough cases.
Simple random sampling technique using of random number generator will be used to select 130 cases and
258 controls.
4.6 Data collection
An extraction form will be used to extract the data from the line-list of the COVID-19 surveillance
COVID-19 data register for both cases and control (attached). Further information will be collected through
phone interviews with cases and controls using pre-coded pre-tested questionnaire (attached).
Trained data collectors will be recruited to collect the data from the research institutions, total of 6 data
collectors.
The data collectors will be trained by the research team.
4.7 Data management plan
● Data will be entered, cleaned, and analyzed using SPSS version 26.0.
Data analysis:
● Odds ratios are calculated in case-control studies to measure how strongly exposure is linked to outcome.
Odds ratios represent the ratio of exposure probabilities in the case group to the odds of responding in the
control group. Each odds ratio should have a confidence interval calculated.
● Data will be presented after analysis in form of uni-variable tables, cross tabulation (bi variable tables),
figures and narrative illustrations.
● The descriptive data will be presented as graphs or tables. By estimating crude and adjusted Odd Ratio (OR),
the researcher will analyze data using univariate and multiple logistic regression.
7
8
4.8 Coordination, monitoring and quality control
Setting up a good feedback mechanism and communicating effectively with respondents are key methods for
ensuring high data quality during primary data collection.
4.9 Ethical considerations:
Research has been approved by the National Ethical Committee
Verbal informed consent will be obtained from participant
Confidentiality will be obtained through serial number
Please describe your proposal:
1.
Does this research involve human subjects?
Yes €
2.
If yes, have you received an ethical approval for this research?
Yes €
3.
No €
No €
Is there a research ethics committee or institutional review board at your institution whichreviews
research on human subjects?
Yes €
4.
If yes, has this committee given ethical approval for the conduct of this research?
Yes €
5.
No €
No €
Will you ensure that confidentiality of collected information (e.g. medical records,
biologicalsamples) obtained from subjects be protected in this research?
Yes €
6.
No €
Have you received any training on ethics of biomedical research?
Yes €
No €
9
5. TIME FRAME OF PROPOSED ACTIVITIES (Gantt chart) as applicable to your
proposal
1st QUARTER
Activity
M1
M2
2nd QUARTER
M3
M4
M5
M6
Research design and planning
Finalize sampling plan,
Develop data collection
Instrument and Pre-test/pilot
data collection
instrument
Carry out data collection
Submission of the interim
X
technical report*
Write up data collection
Prepare data for analysis
Analyze data
Draw conclusions/
recommendations
Final draft of application
Review draft
Final editing
Submit to extramural
funder
Submission of the manuscript for
consideration for publication and
final financial report*
*mandatory
6. BENEFICIARIES OF RESEARCH RESULTS
10
COVID-19 vaccine breakthrough risk factors will be better understood through the research. In
this research. The purpose of this study is to identify risk factors of COVID-19 breakthrough
infection in Sudan and fill knowledge gaps. We will be able to discuss the covid-19 vaccine and
its recommendations in a far more comprehensive way than ever before.
COVID-19 Vaccination campaigns can benefit private and public health personnel. In releasing
the information to the general public, it will allow for a broader discussion about the COVID-19
vaccine in the public sphere and consideration of risk factors (both financial and non-financial).
8. REFERENCES CITED
1. Birhane M, Bressler S, Chang G, Clark T, Dorough L, Fischer M et al. COVID-19 Vaccine
Breakthrough Infections Reported to CDC — United States, January 1–April 30, 2021.
MMWR Morbidity and Mortality Weekly Report. 2021;70(21):792-793.
2. Hamieh, MD C. COVID-19 Vaccines, What do we know so Far? A Narrative Review.
International Journal of Current Science Research and Review. 2021;04(05).
3. Information about the J&J/Janssen COVID-19 Vaccine [Internet]. Centers for Disease Control
and Prevention. 2022 [cited 12 January 2022]. Available from:
https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/janssen.html
4. Butt A, Nafady-Hego H, Chemaitelly H, Abou-Samra A, Khal A, Coyle P et al. Outcomes
Among Patients with Breakthrough SARS-CoV-2 Infection After Vaccination. International
Journal of Infectious Diseases. 2021;110:353-358.
5. Alishaq M, Nafady-Hego H, Jeremijenko A, Al Ajmi J, Elgendy M, Vinoy S et al. Risk factors
for breakthrough SARS-CoV-2 infection in vaccinated healthcare workers. PLOS ONE.
2021;16(10):e0258820.
6. Parameswaran A, Apsingi S, Eachempati KK, Dannana CS, Jagathkar G, Iyer M, Aribandi H.
Incidence and severity of COVID-19 infection post-vaccination: a survey among Indian
doctors. Infection. 2022 Feb 7:1-7.
7. MJ EO, Juanes de Toledo B. Pfizer-BioNTech, la primera vacuna ARNm contra la
COVID-19, parece segura y eficaz
11
8. Jackson LA, Anderson EJ, Rouphael NG, Roberts PC, Makhene M, Coler RN,
McCullough MP, Chappell JD, Denison MR, Stevens LJ, Pruijssers AJ. An mRNA
vaccine against SARS-CoV-2—preliminary report. New England Journal of Medicine.
2020 Jul 14.
9. Walsh EE, Frenck Jr RW. Falsey AR, Kitchin N, Absalon J, Gurtman A, Lockhart S,
Neuzil K, Mulligan MJ, Bailey R, Swanson KA, Li P, Koury K, Kalina W, Cooper D,
Fontes-Garfias C, Shi PY, Türeci Ö, Tompkins KR, Lyke KE, Raabe V, Dormitzer PR,
Jansen KU, Şahin U, Gruber WC: Safety and immunogenicity of two RNA-based
Covid-19 vaccine candidates. N Engl J Med. 2020;383:2439-50.
10. Jabal KA, Ben-Amram H, Beiruti K, Batheesh Y, Sussan C, Zarka S, Edelstein M.
Impact of age, ethnicity, sex and prior infection status on immunogenicity following a
single dose of the BNT162b2 mRNA COVID-19 vaccine: real-world evidence from
healthcare workers, Israel, December 2020 to January 2021. Eurosurveillance. 2021
Feb 11;26(6):2100096.
11. Haas EJ, Angulo FJ, McLaughlin JM, Anis E, Singer SR, Khan F, Brooks N, Smaja M,
Mircus G, Pan K, Southern J. Impact and effectiveness of mRNA BNT162b2 vaccine
against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths
following a nationwide vaccination campaign in Israel: an observational study using
national surveillance data. The Lancet. 2021 May 15;397(10287):1819-29.
12. Butt AA, Omer SB, Yan P, Shaikh OS, Mayr FB. SARS-CoV-2 vaccine effectiveness
in a high-risk national population in a real-world setting. Annals of Internal Medicine.
2021 Oct;174(10):1404-8.
13. Sun J, Zheng Q, Madhira V, Olex AL, Anzalone AJ, Vinson A, Singh JA, French E,
Abraham AG, Mathew J, Safdar N. Association between immune dysfunction and
COVID-19 breakthrough infection after SARS-CoV-2 vaccination in the US. JAMA
internal medicine. 2022 Feb 1;182(2):153-62.
14. Abelenda-Alonso G, Rombauts A, Gudiol C, Oriol I, Simonetti A, Coloma A,
Rodríguez-Molinero A, Izquierdo E, Díaz-Brito V, Sanmartí M, Padullés A.
Immunomodulatory therapy, risk factors and outcomes of hospital-acquired
bloodstream infection in patients with severe COVID-19 pneumonia: a Spanish
12
case–control matched multicentre study (BACTCOVID). Clinical Microbiology and
Infection. 2021 Nov 1;27(11):1685-92.
15. Birhane M, Bressler S, Chang G, Clark T, Dorough L, Fischer M, Watkins LF,
Goldstein JM, Kugeler K, Langley G, Lecy K. COVID-19 vaccine breakthrough
infections reported to CDC—United States, January 1–April 30, 2021.
16. Covid CD, Team VB, COVID C, Team VB, COVID C, Team VB, Birhane M,
Bressler S, Chang G, Clark T, Dorough L. COVID-19 vaccine breakthrough infections
reported to CDC—United States, January 1–April 30, 2021. Morbidity and Mortality
Weekly Report. 2021 May 28;70(21):792.
17. Sun J, Patel RC, Zheng Q, Madhira V, Olex AL, Islam JY, French E, Chiang TP,
Akselrod H, Moffitt R, Alexander GC. Covid-19 disease severity among people with
HIV infection or solid organ transplant in the United States: A
nationally-representative, multicenter, observational cohort study. Medrxiv. 2021 Jan
1.
18. Nicolini LA, Magne F, Signori A, Di Biagio A, Sticchi L, Paganino C, Durando P,
Viscoli C. Hepatitis B virus vaccination in HIV: immunogenicity and persistence of
seroprotection up to 7 years following a primary immunization course. AIDS Research
and Human Retroviruses. 2018 Nov 1;34(11):922-8.
19. Abzug MJ, Warshaw M, Rosenblatt HM, Levin MJ, Nachman SA, Pelton SI,
Borkowsky W, Fenton T, International Maternal Pediatric Adolescent AIDS Clinical
Trials Group P1024 and P1061s Protocol Teams. Immunogenicity and immunologic
memory after hepatitis B virus booster vaccination in HIV-infected children receiving
highly active antiretroviral therapy. The Journal of infectious diseases. 2009 Sep
1;200(6):935-46.
20. Eckerle I, Rosenberger KD, Zwahlen M, Junghanss T. Serologic vaccination response
after solid organ transplantation: a systematic review. PloS one. 2013 Feb
22;8(2):e56974.
21. Gangappa S, Kokko KE, Carlson LM, Gourley T, Newell KA, Pearson TC, Ahmed R,
Larsen CP. Immune responsiveness and protective immunity after transplantation.
Transplant International. 2008 Apr;21(4):293-303.
13
22. Dhodapkar MV, Dhodapkar KM, Ahmed R. Viral immunity and vaccines in
hematologic malignancies: implications for COVID-19. Blood cancer discovery. 2021
Jan;2(1):9.
23. Rozans MK, Smith BR, Burakoff SJ, Miller RA. Long-lasting deficit of functional T
cell precursors in human bone marrow transplant recipients revealed by limiting
dilution methods. The Journal of Immunology. 1986 Jun 1;136(11):4040-8.
24. Haidar G, Agha M, Lukanski A, Linstrum K, Troyan R, Bilderback A, Rothenberger
S, McMahon DK, Crandall M, Enick PN, Sobolewksi M. Immunogenicity of COVID19 vaccination in immunocompromised patients: an observational, prospective cohort
study interim analysis. MedRxiv. 2021 Jan 1.
25. Bertrand D, Hamzaoui M, Lemée V, Lamulle J, Hanoy M, Laurent C, Lebourg L,
Etienne I, Lemoine M, Le Roy F, Nezam D. Antibody and T cell response to
SARS-CoV-2 messenger RNA BNT162b2 vaccine in kidney transplant recipients and
hemodialysis patients. Journal of the American Society of Nephrology. 2021 Sep
1;32(9):2147-52.
26. Kamar N, Abravanel F, Marion O, Couat C, Izopet J, Del Bello A. Three doses of an
mRNA Covid-19 vaccine in solid-organ transplant recipients. New England Journal of
Medicine. 2021 Aug 12;385(7):661-2.
27. Boyarsky BJ, Werbel WA, Avery RK, Tobian AA, Massie AB, Segev DL,
Garonzik-Wang JM. Immunogenicity of a single dose of SARS-CoV-2 messenger
RNA vaccine in solid organ transplant recipients. Jama. 2021 May 4;325(17):1784-6.
28. Marion O, Del Bello A, Abravanel F, Couat C, Faguer S, Esposito L, Hebral AL,
Izopet J, Kamar N. Safety and immunogenicity of anti–SARS-CoV-2 messenger RNA
vaccines in recipients of solid organ transplants. Annals of internal medicine. 2021
Sep;174(9):1336-8.
29. Georgery H, Devresse A, Yombi JC, Belkhir L, De Greef J, Darius T, Buemi A, Scohy
A, Kabamba B, Goffin E, Kanaan N. Very low immunization rate in kidney transplant
recipients after one dose of the BNT162b2 vaccine: beware not to lower the guard!.
Transplantation. 2021 Oct;105(10):e148.
14
30. Sun J, Zheng Q, Madhira V, Olex AL, Anzalone AJ, Vinson A, Singh JA, French E,
Abraham AG, Mathew J, Safdar N. Association between immune dysfunction and
COVID-19 breakthrough infection after SARS-CoV-2 vaccination in the US. JAMA
internal medicine. 2022 Feb 1;182(2):153-62.
31. Bergwerk M, Gonen T, Lustig Y, Amit S, Lipsitch M, Cohen C, Mandelboim M,
Levin EG, Rubin C, Indenbaum V, Tal I. Covid-19 breakthrough infections in
vaccinated health care workers. New England Journal of Medicine. 2021 Oct
14;385(16):1474-84.
15
Instructions for budget items:
No
ITEM OR ACTIVITY
1.
Personnel*
-Principal Investigator
- Research assistants
- Consultants
- Interviewers
- Data managers or
analysts
2.
Telecommunications and
Data collectors’ incentive
3.
Equipment
- laptops renting
-
4.
Local Travel
-
5.
Surveillance
-
6.
Training
-Trainer
-Trainee
-Meals and Refreshment
-
7.
Dissemination of
results**
-Publication costs
- Data analysis
-
8.
Other Costs***
-
Total in SDG
Amount
Requested
JUSTIFICATION
-
323
323
Telecommunications and
incentives to 323 participants