Effectiveness of Covid-19 Vaccination in Eswatini Against SARS-CoV-2 Associated Hospitalization and Death

• ClinicalTrials.gov Identifier: NCT04914832
• Recruitment Status: Not yet recruiting
• First Posted: June 7, 2021
• Last Update Posted: June 7, 2021
• Sponsor: Shabir Madhi
• Collaborator: AstraZeneca
• Information provided by (Responsible Party): Shabir Madhi, University of Witwatersrand, South Africa

Study Description

Brief Summary:

Since late December 2019, the novel human coronavirus (SARS-CoV-2) first reported in China, has spread worldwide. Vaccines to prevent SARS-CoV-2 infections have been developed in record time and several candidate vaccines have completed Phase 2a/b and Phase 3 clinical trials.

Coronaviruses (CoVs) are spherical, enveloped viruses with positive-sense single-stranded RNA genomes. One fourth of their genome is responsible for coding structural proteins, such as the Spike (S) glycoprotein, envelope, membrane, and nucleocapsid proteins. Envelope, membrane, and nucleocapsid proteins are mainly responsible for virion assembly whilst the S protein is involved in receptor binding, mediating virus entry into host cells during CoVs infection via different receptors. SARS-CoV-2 belongs to the phylogenetic lineage B of the genus Betacoronavirus and it recognizes the ACE2 as the entry receptor. It is the seventh CoV known to cause human infections and the third known to cause severe disease after SARS-CoV and MERS-CoV.

AZD1222 is a recombinant replication-defective chimpanzee adenovirus vaccine expressing the SARS-CoV-2 S surface glycoprotein. Development of AZD1222, previously referred to as ChAdOx1 nCoV-19, was initiated by the University of Oxford, UK, with subsequent transfer of development activities to AstraZeneca. The ChAdOx1 platform has been used in 14 clinical studies sponsored by the University of Oxford with immunogens from multiple pathogens such as influenza, tuberculosis, malaria, chikungunya, Zika, MERS-CoV, and Meningitis B. Over 360 healthy adult participants have received ChAdOx1-vectored vaccines in these studies. These vaccines demonstrated robust immunogenicity after a single dose and favourable safety profiles, with no vaccine-related serious adverse events (SAEs).

Condition or disease	Intervention/treatment	Phase
Vaccine Preventable Disease	Biological: AZD1222	Phase 4

Detailed Description:

This will be open-label, single-arm implementation study in Eswatini. All individuals who register on the National Vaccination Registry will be eligible for enrolment. Participants will receive appointments for vaccination using the registry. Vaccination will be overseen by trained personnel. At enrolment participants will receive an intramuscular injection of AZ1222, a second dose will be given 10 weeks after the first injection. Surveillance for vaccine effectiveness will be performed at designated hospitals.

A prospective hospital-based, case-control study with test-negative controls (test-negative case-control design) and optionally other hospital controls (standard case-control design) will be conducted in parallel with the implementation study. Data will be collected through a network of hospitals located in Eswatini. A hospital-based case control study is an efficient design well suited to study for effectiveness against severe disease, and potentially allows for detailed medical information and additional data collection directly from the patient or healthcare provider. In addition, the study aims to determine the vaccine effectiveness (VE) of AZ1222 against severe disease due to the B.1.351 variant circulating in Southern Africa and other new variants that might evolve.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 600 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment

Intervention Model Description

1. Open-label, single-arm implementation study.
2. Prospective hospital and mortuary-based case-control study with test-negative controls (test-negative case-control study) and other hospital controls (standard case-control study).

• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Effectiveness of Covid-19 Vaccination in Eswatini Against SARS-CoV-2 Associated Hospitalization and Death
• Estimated Study Start Date: June 30, 2021
• Estimated Primary Completion Date: May 31, 2022
• Estimated Study Completion Date: May 31, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: All individuals who register on the National Vaccination Registry; This will be open-label, single-arm implementation study in Eswatini. All individuals who register on the National Vaccination Registry will be eligible for enrolment. Participants will receive appointments for vaccination using the registry.	Biological: AZD1222; AZD1222 is a recombinant replication-defective chimpanzee adenovirus vaccine expressing the SARS-CoV-2 S surface glycoprotein.

Outcome Measures

Primary Outcome Measures :

1. Vaccine effectiveness in HIV-uninfected [ Time Frame: 1 year ]
   Laboratory-confirmed SARS-CoV-2 illness (COVID-19) hospitalizations and deaths in HIV-uninfected individuals who have been vaccinated with at least 1 dose.
2. To estimate the AZD1222 vaccine effectiveness [ Time Frame: 1 year ]
   Laboratory-confirmed COVID-19 hospitalizations and deaths in individuals irrespective of HIV status [people living with (PLWH) and without HIV] who have been vaccinated with at least 1 dose.

Secondary Outcome Measures :

1. To estimate the AZD1222 vaccine effectiveness overall [ Time Frame: 1 year ]
   Laboratory-confirmed COVID-19 hospitalizations and deaths in HIV-uninfected individuals and irrespective of HIV status who have been vaccinated with at least 1 dose.
2. Vaccine effectiveness in fully vaccinated HIV-uninfected [ Time Frame: 1 year ]
   Laboratory-confirmed COVID-19 hospitalizations and deaths in HIV-uninfected individuals who have been fully vaccinated according to the national immunization recommendations.
3. Vaccine effectiveness in fully vaccinated overall [ Time Frame: 1 year ]
   Laboratory-confirmed COVID-19 hospitalizations and deaths in individuals irrespective of HIV status who have been fully vaccinated according to the national immunization recommendations.
4. Vaccine effectiveness according to the vaccine interval between doses [ Time Frame: 1 year ]
   Laboratory-confirmed COVID-19 hospitalizations and deaths in individuals irrespective of HIV status who have been fully vaccinated according to the vaccine interval in between dose (≤4 weeks, 5-8 weeks, 8-11 weeks, ≥12 weeks).
5. Vaccine effectiveness by genetic variant [ Time Frame: 1 year ]
   The effect of AZD1222 vaccine on laboratory-confirmed COVID-19 hospitalizations and deaths in individuals irrespective of HIV status who have been vaccinated (with at least 1 dose/ fully vaccinated according to the national recommendations), by viral genetic variants (particularly B.1.351 and non-B.1.351 variants).
6. Vaccine effectiveness in within populations of special interest [ Time Frame: 1 year ]
   Laboratory-confirmed COVID-19 hospitalizations and deaths in individuals irrespective of HIV status who have been vaccinated (with at least 1 dose/ fully vaccinated according to the national recommendations), within populations of special interest (e.g. PLWH, specific age groups [special focus on the elderly], Chronic Respiratory Disease, Chronic Cardiovascular Disease, Chronic Kidney Disease, Chronic Liver Disease, Chronic neurologic Disease, Auto-Immune Disease, pregnant women, immunocompromised or specific chronic conditions).
7. Vaccine effectiveness by time since vaccination [ Time Frame: 1 year ]
   The effect of AZD1222 vaccine against laboratory-confirmed COVID-19 hospitalization and death in individuals irrespective of HIV status who have been vaccinated (with at least 1 dose/ fully vaccinated according to the national recommendations), by time since vaccination, including ≤14 days prior to symptom onset.

Other Outcome Measures:

1. Vaccine effectiveness by level of disease severity [ Time Frame: 1 year ]
   The AZD1222 vaccine effectiveness against laboratory-confirmed COVID-19 hospitalization and death in individuals irrespective of HIV status who have been vaccinated (with at least 1 dose/ fully vaccinated according to the national recommendations/ fully vaccinated according to the vaccine label), by level of severity. Three mutually exclusive categories: (i) hospital admission without intensive care unit (ICU) admission and without in-hospital death, (ii) ICU admission without in hospital death and (iii) in-hospital death.
2. Impact on length of hospital stay [ Time Frame: 1 year ]
   To estimate the AZD1222 vaccine effect among laboratory-confirmed COVID-19 patients (vaccinated with at least 1 dose/ fully vaccinated according to the national recommendations) on the length of hospital stay (in days).
3. Vaccine effectiveness stratified by SARS-CoV-2 seropositivity status [ Time Frame: 1 year ]
   12. To estimate the AZD1222 vaccine effectiveness against laboratory-confirmed COVID-19 hospitalization and death in individuals irrespective of HIV status who have been vaccinated (with at least 1 dose/ fully vaccinated according to the national recommendations), stratified by SARS-CoV-2 seropositivity status (based on N-protein IgG) at admission.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Any individual aged 18 and older eligible to receive AZ1222 vaccine following the national immunization recommendations.
• Willing and able to provide informed consent.

Exclusion Criteria:

• Any significant acute or chronic medical condition that in the opinion of the vaccinator makes the participant unsuitable for participation in the study or jeopardises the safety of the participant.
• Participant reports being pregnant.
• History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine.

Test negative vaccine effectiveness case-control study

The study population consists of individuals presenting at the participating hospitals and health centres during the study period, who:

Either

• Are hospitalized (or died) for an illness consistent with possible COVID-19. Or (in case of other hospital controls)
• Presented to the emergency department (ED) for reasons other than a COVID-19 like illness (e.g. trauma or elective surgery).

And

• Meet the inclusion criteria.

Inclusion criteria:

• Ever eligible to receive AZ1222 vaccine following the national immunization recommendations prior to hospital admission.

And

• Willing and able to provide informed consent.

Exclusion criteria:

• None

Contacts and Locations

Contacts

Contact: marta nunes, PhD; +27729058739; marta.nunes@wits-vida.org

Contact: Tenele Dlamini, MD; +26876373509; neledlamini.td@gmail.com

Locations

Swaziland

Vaccination Center

Mbabane, Swaziland

Contact: Tenele Tenele Dlamini, MD +26876373509 neledlamini.td@gmail.com

Sub-Investigator: Vusie Lokotfwako, MD

Sponsors and Collaborators

Shabir Madhi

AstraZeneca

More Information

Publications of Results:

Fischer RJ, van Doremalen N, Adney DR, Yinda CK, Port JR, Holbrook MG, Schulz JE, Williamson BN, Thomas T, Barbian K, Anzick SL, Ricklefs S, Smith BJ, Long D, Martens C, Saturday G, de Wit E, Gilbert SC, Lambe T, Munster VJ. ChAdOx1 nCoV-19 (AZD1222) protects Syrian hamsters against SARS-CoV-2 B.1.351 and B.1.1.7. Nat Commun. 2021 Oct 7;12(1):5868. doi: 10.1038/s41467-021-26178-y.

Other Publications:

Folegatti PM, Ewer KJ, Aley PK, Angus B, Becker S, Belij-Rammerstorfer S, Bellamy D, Bibi S, Bittaye M, Clutterbuck EA, Dold C, Faust SN, Finn A, Flaxman AL, Hallis B, Heath P, Jenkin D, Lazarus R, Makinson R, Minassian AM, Pollock KM, Ramasamy M, Robinson H, Snape M, Tarrant R, Voysey M, Green C, Douglas AD, Hill AVS, Lambe T, Gilbert SC, Pollard AJ; Oxford COVID Vaccine Trial Group. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet. 2020 Aug 15;396(10249):467-478. doi: 10.1016/S0140-6736(20)31604-4. Epub 2020 Jul 20. Erratum In: Lancet. 2020 Aug 15;396(10249):466. Lancet. 2020 Dec 12;396(10266):1884.

Greaney AJ, Loes AN, Crawford KHD, Starr TN, Malone KD, Chu HY, Bloom JD. Comprehensive mapping of mutations in the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human plasma antibodies. Cell Host Microbe. 2021 Mar 10;29(3):463-476.e6. doi: 10.1016/j.chom.2021.02.003. Epub 2021 Feb 8.

Tegally, H., E. Wilkinson, M. Giovanetti, A. Iranzadeh, V. Fonseca, J. Giandhari, D. Doolabh, S. Pillay, E. J. San, N. Msomi, K. Mlisana, A. von Gottberg, S. Walaza, M. Allam, A. Ismail, T. Mohale, A. J. Glass, S. Engelbrecht, G. Van Zyl, W. Preiser, F. Petruccione, A. Sigal, D. Hardie, G. Marais, M. Hsiao, S. Korsman, M.-A. Davies, L. Tyers, I. Mudau, D. York, C. Maslo, D. Goedhals, S. Abrahams, O. Laguda-Akingba, A. Alisoltani-Dehkordi, A. Godzik, C. K. Wibmer, B. T. Sewell, J. Lourenço, L. C. J. Alcantara, S. L. K. Pond, S. Weaver, D. Martin, R. J. Lessells, J. N. Bhiman, C. Williamson and T. de Oliveira (2020).

Volz, E., S. Mishra, M. Chand, J. C. Barrett, R. Johnson, L. Geidelberg, W. R. Hinsley, D. J. Laydon, G. Dabrera, Á. O'Toole, R. Amato, M. Ragonnet-Cronin, I. Harrison, B. Jackson, C. V. Ariani, O. Boyd, N. J. Loman, J. T. McCrone, S. Gonçalves, D. Jorgensen, R. Myers, V. Hill, D. K. Jackson, K. Gaythorpe, N. Groves, J. Sillitoe, D. P. Kwiatkowski, S. Flaxman, O. Ratmann, S. Bhatt, S. Hopkins, A. Gandy, A. Rambaut and N. M. Ferguson (2021).

Voysey, M., S. A. C. Clemens, S. A. Madhi, L. Y. Weckx, P. M. Folegatti, P. K. Aley, B. Angus, V. L. Baillie, S. L. Barnabas, Q. E. Bhorat, S. Bibi, C. Briner, P. Cicconi, A. M. Collins, R. Colin-Jones, C. L. Cutland, T. C. Darton, K. Dheda, C. J. A. Duncan, K. R. W. Emary, K. J. Ewer, L. Fairlie, S. N. Faust, S. Feng, D. M. Ferreira, A. Finn, A. L. Goodman, C. M. Green, C. A. Green, P. T. Heath, C. Hill, H. Hill, I. Hirsch, S. H. C. Hodgson, A. Izu, S. Jackson, D. Jenkin, C. C. D. Joe, S. Kerridge, A. Koen, G. Kwatra, R. Lazarus, A. M. Lawrie, A. Lelliott, V. Libri, P. J. Lillie, R. Mallory, A. V. A. Mendes, E. P. Milan, A. M. Minassian, A. McGregor, H. Morrison, Y. F. Mujadidi, A. Nana, P. J. O'Reilly, S. D. Padayachee, A. Pittella, E. Plested, K. M. Pollock, M. N. Ramasamy, S. Rhead, A. V. Schwarzbold, N. Singh, A. Smith, R. Song, M. D. Snape, E. Sprinz, R. K. Sutherland, R. Tarrant, E. C. Thomson, M. E. Torok, M. Toshner, D. P. J. Turner, J. Vekemans, T. L. Villafana, M. E. E. Watson, C. J. Williams, A. D. Douglas, A. V. S. Hill, T. Lambe, S. C. Gilbert, A. J. Pollard and C. V. T. G. Oxford (2021).

Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, Chen HD, Chen J, Luo Y, Guo H, Jiang RD, Liu MQ, Chen Y, Shen XR, Wang X, Zheng XS, Zhao K, Chen QJ, Deng F, Liu LL, Yan B, Zhan FX, Wang YY, Xiao GF, Shi ZL. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020 Mar;579(7798):270-273. doi: 10.1038/s41586-020-2012-7. Epub 2020 Feb 3. Erratum In: Nature. 2020 Dec;588(7836):E6.

• Responsible Party: Shabir Madhi, Professor, University of Witwatersrand, South Africa
• ClinicalTrials.gov Identifier: NCT04914832
• Other Study ID Numbers: Eswatini Implementation & VE
• First Posted: June 7, 2021
• Last Update Posted: June 7, 2021
• Last Verified: June 2021

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Shabir Madhi, University of Witwatersrand, South Africa:

Vaccine effectiveness against hospitalization and death

Additional relevant MeSH terms:

Vaccine-Preventable Diseases; Infections