Dear editor,
A recent publication in this journal by Nisar et al. 1 assessed the effectiveness of various COVID-19 vaccines in Pakistan using a test-negative case-control design. They report moderate effectiveness of various vaccines and higher effectiveness mRNA vaccines compared with inactivated vaccines. Although they assessed the impact of concurrent medical conditions, they were only a few cases of immunosuppression contributing to<3% of the study population and approximately 87% of the participants received Sinopharm and Sinovac, and 1% received the Oxford/AstraZeneca vaccine. AstraZeneca (AZD1222), formerly called ChAdOx1, previously demonstrated robust immunogenicity after a single dose with favorable safety profiles.2, 3 Despite Botswana’s high HIV prevalence, treatment has been hugely successful with over 90% of all adults living with HIV currently receiving antiretroviral therapy (ART).4 There are no data on the safety and effectiveness of AZD1222 in this high HIV prevalence setting.
We conducted a single-arm, open-label interventional multi-site study (D8111C00013/ESR-21–21311) to monitor vaccine safety and the occurrence of symptomatic COVID-19 infections, hospitalizations and deaths among individuals vaccinated with AZD1222 between September 15, 2021, and May 18, 2022, at five sites in Botswana. The study was approved by the Health and Research Development Committee (HRDC#00936). All participants provided written informed consent.
We screened 9419 and enrolled 9140 participants ( Fig. 1). Of the participants included in this study, 9124 (99.8%) were receiving at least one dose of AZD1222 and remaining in the study 22 days after the first dose without having a SARS-CoV-2 RT-PCR positive confirmed COVID-19 infection, Vaccinated Set (VS); 2275 of these participants were included in the Single Dose Set (SDS) (did not receive a second dose), and 6838 participants were included in the Full vaccinated set (FVS) (2 doses of AZD1222, at least 15 days after their second dose without a PCR-confirmed COVID-19 infection).
Fig. 1.
Overall diagram on study population.
Most participants were male (54.1%) and Black African (99.9%) with a median age of 30 years (IQR: 23–42 years), Table 1. Of the participants enrolled, 21.4% were people with HIV (PWH). Amongst PWH, 96.5% were on ART. There were no laboratory-confirmed COVID-19 hospitalizations or deaths during the study reporting period. There were 27 laboratory-confirmed symptomatic COVID-19 infections post-vaccination; 14 were within 22 days of the first vaccination. Of the 13 post-22 days after the first vaccination, 9 were within 14 days post-Dose 2 (Supplementary Fig. 1). The overall incidence of laboratory-confirmed symptomatic COVID-19 infection in the study, after two doses of AZD1222 in the FVS, was 1.67 (95% CI: 0.34–4.86) per 1000 participant years (1000-PY) (Supplementary Tables 1, 2). The three infections that occurred> 15 days post-second vaccination (18, 20, and 22 days) were from HIV-uninfected individuals (female 40-<65 years, male 40-<65 years and one male<40 years of age). All infections occurred when Omicron was the dominant circulating variant.5 The overall incidence of laboratory-confirmed symptomatic COVID-19 infection after one dose of AZD1222 in the VS was 3.46 (95% CI: 1.84–5.90) per 1000-PY. This incidence was significantly higher at 8.07 (95% CI: 3.25–16.64) in PWH compared to 2.34 (95% CI: 0.86–5.09) in HIV-uninfected participants. In contrast, the overall incidence of symptomatic COVID-19 infection in FVS was 1.67 (95% CI: 0.34–4.87) per 1000-PY. There were no differences by HIV status in the FVS (Supplementary Table 2). Point estimates of incidence in participants with at least one dose were higher in PWH (8.07; 95% CI: 3.25–16.57) compared with HIV-uninfected individuals (2.34; 95% CI: 0.86–5.09), although the difference was not statistically significant.
Table 1.
AZD 1222 study participants baseline characteristics by vaccination sets.
| Variable | FAS | SDS | VS | FVS |
|---|---|---|---|---|
| Total number enrolled | 9140 | 2275 | 9124 | 6838 |
| Site n(%) | ||||
| Gaborone | 3759 (41.1) | 851 (37.4) | 3745 (41) | 2888 (42.2) |
| Maun | 1751 (19.2) | 612 (26.9) | 1751 (19.2) | 1138 (16.6) |
| Serowe | 1269 (13.9) | 257 (11.3) | 1269 (13.9) | 1011 (14.8) |
| Francistown | 1454 (15.9) | 324 (14.2) | 1454 (15.9) | 1130 (16.5) |
| Selebi Phikwe | 907 (9.9) | 231 (10.2) | 905 (9.9) | 671 (9.8) |
| Gender n(%) | ||||
| Female | 4192 (45.9) | 932 (41) | 4184 (45.9) | 3245 (47.5) |
| Male | 4948 (54.1) | 1343 (59) | 4940 (54.1) | 3593 (52.5) |
| Ethnicity n(%) | ||||
| Black African | 9130 (99.9) | 2272 (99.9) | 9114 (99.9) | 6831 (99.9) |
| Asian | 5 (0.1) | 3 (0.1) | 5 (0.1) | 2 (0) |
| Caucasian | 1 (0) | 0 (0) | 1 (0) | 1 (0) |
| Other | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Missing | 4 (0) | 0 (0) | 4 (0) | 4 (0.1) |
| Median age in years (IQR) | 30 (23–42) | 26 (21–33) | 30 (23–42) | 32 (23–43) |
| <40 | 6329 (69.2) | 1976 (86.9) | 6315 (69.2) | 4334 (63.4) |
| 40–65 | 2719 (29.7) | 287 (12.6) | 2717 (29.8) | 2424 (35.4) |
| ≥65 | 92 (1) | 12 (0.5) | 92 (1) | 80 (1.2) |
| HIV n(%) | ||||
| Negative | 6283 (68.7) | 1600 (70.3) | 6274 (68.8) | 4671 (68.3) |
| Positive | 1960 (21.4) | 346 (15.2) | 1959 (21.5) | 1606 (23.5) |
| Unknown | 897 (9.8) | 329 (14.5) | 891 (9.8) | 561 (8.2) |
| ART n(%) | 1884 (96.5) | 331 (95.7) | 1883 (96.5) | 1545 (96.7) |
| Pregnancy n (%) | 72 (1.9) | 68 (7.7) | 72 (2) | 4 (0.1) |
| Median BMI (IQR) tnote2 | 22 (20–27) | 21 (19–26) | 22 (20–27) | 23 (20–28) |
| < 18.5 | 1415 (15.5) | 398 (17.5) | 1412 (15.5) | 1012 (14.8) |
| 18.5-<25 | 4563 (49.9) | 1269 (55.8) | 4557 (49.9) | 3284 (48) |
| 25-<30 | 1673 (18.3) | 344 (15.1) | 1671 (18.3) | 1324 (19.4) |
| ≥30 | 1489 (16.3) | 264 (11.6) | 1484 (16.3) | 1218 (17.8) |
| Diabetes n (%) | ||||
| No | 8970 (98.1) | 2247 (98.8) | 8954 (98.1) | 6696 (97.9) |
| Yes | 169 (1.8) | 28 (1.2) | 169 (1.9) | 141 (2.1) |
| Missing | 1 (0) | 0 (0) | 1 (0) | 1 (0) |
| Hypertension n (%) | ||||
| No | 8770 (96) | 2242 (98.5) | 8756 (96) | 6503 (95.1) |
| Yes | 369 (4) | 33 (1.5) | 367 (4) | 334 (4.9) |
| Missing | 1 (0) | 0 (0) | 1 (0) | 1 (0) |
| Prior COVID infection n (%) | ||||
| No | 8414 (92.1) | 2131 (93.7) | 8398 (92) | 6258 (91.5) |
| Yes | 725 (7.9) | 144 (6.3) | 725 (7.9) | 579 (8.5) |
| Missing | 1 (0) | 0 (0) | 1 (0) | 1 (0) |
| Smoking status n (%) | ||||
| Current | 1958 (21.4) | 568 (25) | 1957 (21.4) | 1387 (20.3) |
| Occasional | 337 (3.7) | 106 (4.7) | 336 (3.7) | 229 (3.3) |
| Previous | 489 (5.4) | 117 (5.1) | 489 (5.4) | 371 (5.4) |
| Never | 6355 (69.5) | 1484 (65.2) | 6341 (69.5) | 4850 (70.9) |
| Missing | 1 (0) | 0 (0) | 1 (0) | 1 (0) |
| Alcohol status n (%) | ||||
| Current | 2854 (31.2) | 825 (36.3) | 2851 (31.2) | 2023 (29.6) |
| Occasional | 1942 (21.2) | 482 (21.2) | 1940 (21.3) | 1454 (21.3) |
| Previous | 651 (7.1) | 158 (6.9) | 650 (7.1) | 492 (7.2) |
| Never | 3692 (40.4) | 810 (35.6) | 3682 (40.4) | 2868 (41.9) |
| Missing | 1 (0) | 0 (0) | 1 (0) | 1 (0) |
| Highest education level n (%) | ||||
| None | 267 (2.9) | 47 (2.1) | 267 (2.9) | 218 (3.2) |
| Primary | 740 (8.1) | 135 (5.9) | 740 (8.1) | 605 (8.8) |
| Junior Secondary | 3229 (35.3) | 821 (36.1) | 3226 (35.4) | 2400 (35.1) |
| Senior Secondary | 2624 (28.7) | 711 (31.3) | 2620 (28.7) | 1905 (27.9) |
| Tertiary | 2279 (24.9) | 561 (24.7) | 2270 (24.9) | 1709 (25) |
| Employment status n (%) | ||||
| Formal wage employment part-time | 481 (5.3) | 125 (5.5) | 480 (5.3) | 355 (5.2) |
| Formal wage employment fulltime) | 2670 (29.2) | 537 (23.6) | 2669 (29.3) | 2127 (31.1) |
| Self-employed part time) | 486 (5.3) | 118 (5.2) | 486 (5.3) | 368 (5.4) |
| Self-employed full time) | 1029 (11.3) | 204 (9) | 1026 (11.2) | 821 (12) |
| Ad-hoc work | 32 (0.4) | 5 (0.2) | 32 (0.4) | 27 (0.4) |
| Seasonal employment | 195 (2.1) | 46 (2) | 195 (2.1) | 148 (2.2) |
| Other | 4246 (46.5) | 1240 (54.5) | 4235 (46.4) | 2991 (43.7) |
| Marital status n (%) | ||||
| Single | 1980 (21.7) | 460 (20.2) | 1980 (21.7) | 1518 (22.2) |
| Cohabiting | 7159 (78.3) | 1815 (79.8) | 7143 (78.3) | 5319 (77.8) |
| Married | ||||
| Divorced | 6917 (75.7) | 1873 (82.3) | 6902 (75.7) | 5020 (73.4) |
| Widowed | 1260 (13.8) | 307 (13.5) | 1260 (13.8) | 953 (13.9) |
| Other | 815 (8.9) | 79 (3.5) | 814 (8.9) | 733 (10.7) |
FAS-Full analysis set.
FVS-Full vaccinated set (two doses of AZD1222, at least 15 days after their second dose without having a PCR-confirmed COVID-19 infection).
SDS-Single Dose Set (did not receive a second dose).
VS-Vaccinated Set (receiving at least one dose of AZD1222 and remaining in the study 22 days after the first dose without having a SARS-CoV-2 RT-PCR positive confirmed COVID-19 infection).
There was a total of 673 adverse events (AEs) incidence of 158 per 1000-PY; (Supplementary Table 3). Three-hundred and fifty-six participants (3.9%) experienced at least one AE (Supplementary Table 5). The distribution of the number of AEs experienced per participant was comparable between HIV-uninfected and PWH (Supplementary Table 5). The 456 reported AEs deemed related to study product were generally mild to moderate in severity, headache (114) (26.7 per 1000-PY), fatigue (51) (12 per 1000-PY); pyrexia (33) (7.7 per 1000-PY, and dizziness (29) (0.32 per 1000-PY). Participants with prior COVID-19 infection had a significantly higher incidence of AEs compared to those who were COVID-19-naive, with 321 AEs occurring per 1000-PY versus 144 per 1000-PY in COVID-naive individuals (p-value<0.0001; Supplementary Table 4). Furthermore, the incidence of AEs was higher in both COVID-19-naive and previously infected participants after the first vaccination, as compared to after the second vaccination. The incidence of AEs in HIV-uninfected individuals and PWH was 160 per 1000-PY and 153 per 1000-PY, respectively. Seventeen SAEs from 15 participants were reported during the study period (incidence of 4 per 1000-PY), of which five SAEs were abortions (Supplementary Tables 1 and 3). Overall, there were 15 localized AEs and 658 systemic AEs (Supplementary Tables 8–10).
The incidence of AESI in HIV-uninfected individuals was 1.72 per 1000 participant-years compared to 2.05 in PWH. Three SAEs were within 28 days post-first dose and no SAEs occurred after second dose (Supplementary Table 3). This study confirms that AZD1222 is equally efficacious in preventing severe infections and is consistent with findings from other populations.3, 6, 7, 8, 9 The overall incidence of laboratory-confirmed symptomatic COVID-19 infection after two doses of AZD1222 in the FVS was 1.67 (95% CI: 0.34–4.86) per 1000-PY which is lower than in the placebo group of a similar study in Brazil, UK, and South Africa.3
Participants with prior COVID-19 infection had a higher incidence of AEs after the first vaccination (Supplementary Table 4). This is consistent with previous reports linking prior infection to increased risk of AEs post-vaccination.10 We also found a higher incidence of severe systemic AEs in participants with prior COVID-19 infection compared to those without prior infection.
Our results should be interpreted in the context of the changing COVID-19 pandemic landscape and vaccine access. Limitations include telephonic reporting which could have resulted in underreporting and potentially misgrading of AEs partially mitigated by collecting complete information through standardized AEs case report forms.
In conclusion, AZD1222 was effective in preventing severe COVID-19 infections in both PLWH and HIV-uninfected people. No COVID-19-related hospitalizations or deaths were observed.
Funding
This work was supported by AstraZeneca under an externally sponsored collaborative research agreement (D8111C00013/ESR-21–21311). SM was partially supported through the Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE 2.0), by the Bill and Melinda Gates Foundation (INV-033558) and the National Institutes of Health NIH Fogarty International Center K43 TW012350-01. The contents of the manuscript are solely the responsibility of the authors and do not necessarily represent the official positions of the funding agencies.
Ethical statement
Written consent was obtained from the study participants before their enrollment.
Conflicts of interest
ST and PG are employees of, and hold or may hold stock in, AstraZeneca. AW is an employee of X4 Group contracted to AstraZeneca for this work. LC is an employee of SRG Recruitment contracted to AstraZeneca for this work. All other authors declare that they have no conflict of interest.
Acknowledgments
The manuscript's contents are solely the responsibility of the authors and do not necessarily represent the official positions of the funding agencies.
The authors thank AZD 1222 Study Participants, dikgosi and other community leaders, and the clinic staff, District Health Management Teams, and Community Health Facilities at study sites; the AZD 1222 Study Team at the Botswana Harvard AIDS Institute Partnership, and the Botswana Ministry of Health; Botswana Harvard HIV Reference laboratory staff, Cornelius Gaetsaloe, Dineo Thebe, Kevin Opelokgale and Bernadette Kgakge for administrative support; Wakamoso Mathaka, Wonderful Choga, Moffat Motlhanka, Itumeleng Mosweu for data management support, our collaborators, the University of the Witwatersrand-VIDA and OnQ.
Footnotes
Supplementary data associated with this article can be found in the online version at doi:10.1016/j.jinf.2023.02.037.
Appendix A. Supplementary material
Supplementary material
References
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Supplementary Materials
Supplementary material