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Assessing the effectiveness of COVID-19 vaccines in Pakistan: a test-negative case-control study

Published:January 25, 2023DOI:https://doi.org/10.1016/j.jinf.2023.01.016
      Dear Editor,
      A recent publication in this journal by Hannawi et al. assessed a novel SARS-CoV-2 bivalent recombinant vaccine, SCTV01C, given as a booster to those who had previously received the primary series of an inactivated vaccine (
      • Hannawi S
      • Saifeldin L
      • Abuquta A
      • Alamadi A
      • Mahmoud SA
      • Li J
      • et al.
      Safety and immunogenicity of a bivalent SARS-CoV-2 protein booster vaccine, SCTV01C in adults previously vaccinated with inactivated vaccine: A randomized, double-blind, placebo-controlled phase 1/2 clinical trial.
      ). The data showed that SCTV01C was well tolerated with a reactogenicity profile comparable to inactivated vaccines and induced substantial immune responses against Delta and Omicron variants (
      • Hannawi S
      • Saifeldin L
      • Abuquta A
      • Alamadi A
      • Mahmoud SA
      • Li J
      • et al.
      Safety and immunogenicity of a bivalent SARS-CoV-2 protein booster vaccine, SCTV01C in adults previously vaccinated with inactivated vaccine: A randomized, double-blind, placebo-controlled phase 1/2 clinical trial.
      ). Inactivated vaccines are widely used in low-and middle-income countries (
      • Jara A
      • Undurraga EA
      • González C
      • Paredes F
      • Fontecilla T
      • Jara G
      • et al.
      Effectiveness of an Inactivated SARS-CoV-2 Vaccine in Chile.
      ). In Pakistan, Sinopharm (inactivated vaccine) was the first vaccine against COVID-19 to be introduced in February 2021. However, there is a paucity of vaccine effectiveness data from this region which undermines evidence-based decision-making. In addition, the protective effect of inactivated vaccines is considerably lower against emergent SARS-CoV-2 variants, signifying a need for booster doses (
      • Lopez Bernal J
      • Andrews N
      • Gower C
      • Gallagher E
      • Simmons R
      • Thelwall S
      • et al.
      Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant.
      ). In Pakistan, eight different COVID-19 vaccines have been used since the launch of the government vaccination programme against covid 19, this provides an ideal setting for assessing the relative impact against symptomatic infection (
      WH. O
      Evaluation of COVID-19 vaccine effectiveness: interim guidance.
      ).
      We conducted a test-negative case-control study to assess the effectiveness of various COVID-19 vaccines, including mRNA, inactivated and viral vector vaccines, that were deployed in Pakistan. Adult residents of Karachi, Pakistan who tested for COVID-19 with RT-PCR at the Aga Khan University Hospital testing facility between June-September 2021 were contacted via phone calls. Participants who were symptomatic within a week prior to the test and provided verbal consent were enrolled in the study. Detailed information was collected on exposure, symptomatic history and vaccination status using a structured questionnaire. Individuals who were positive on PCR were classified as cases and those who tested negative were classified as controls. Effectiveness of different vaccines were calculated by comparing vaccination rates between cases and controls after adjusting for known confounders.
      In total, 1597 cases and 1590 controls were enrolled, of which 38·1% of the cases and 53·3% controls were fully vaccinated respectively. The mean duration of interval between last dose of vaccination and RT-PCR test among those who received a two-dose regimen was 27·3 days. Sinopharm was the most used vaccine (61·6%) followed by Sinovac (25·6%) and CanSinoBIO (8·9%). Only 33 individuals (2·3%) had received Sputnik-V, while the mRNA vaccines, Pfizer and Moderna, were each received by eight participants (0·5% each); Oxford/AstraZeneca was received by six (0·4%) and only two participants (0·1%) had received Janssen (Table 1).
      Table 1Socio-demographic characteristics and vaccination status among cases and controls
      CharacteristicsTotalCasesControls
      N=3187(%)N=1597(%)N=1590(%)p-value
      Age, years (mean ± SD)38.5 ± 13.340.6 ± 14.236.4 ± 12.0
      18 – 29 years928 (29.1)382 (23.9)546 (34.3)<0.001
      30 – 39 years1045 (32.8)513 (32.1)532 (33.5)
      40 – 49 years544 (17.1)283 (17.7)261 (16.4)
      50 – 59 years358 (11.2)207 (13.0)151 (9.5)
      60 – 69 years230 (7.2)149 (9.3)81 (5.1)
      70+ years82 (2.6)63 (3.9)19 (1.2)
      Gender
      Female1400 (43.9)703 (44.0)697 (43.8)0.97
      Male1787 (56.1)894 (56.0)893 (56.2)
      Healthcare workers626 (19.6)211 (13.2)415 (26.1)<0.001
      Ethnicityn= 3183n= 1595n= 1588
      Sindhi352 (11)156 (9.8)196 (12.3)0.06
      Punjabi244 (7.7)123 (7.7)121 (7.6)
      Pushto79 (2.5)39 (2.5)40 (2.5)
      Balochi50 (1.6)30 (1.9)20 (1.3)
      Urdu speaking2089 (65.5)1075 (67.4)1014 (63.9)
      Others
      Ethnic groups from other parts of Pakistan
      369 (11.7)172 (10.8)197 (12.4)
      Education status14.1 ± 3.513.9 ± 3.714.3 ± 3.2
      No formal education60 (1.9)41 (2.6)19 (1.2)<0.001
      Elementary (1 to 8 years)107 (3.4)57 (3.7)50 (3.2)
      Secondary (9 to 12 years)635 (20.3)352 (22.5)283 (18.1)
      Graduation (12 to 16 years)1901 (60.8)910 (58.3)991 (63.2)
      Higher Education (17+ years)426 (13.6)202 (12.9)224 (14.3)
      Previous COVID-19 infection297 (9.3)59 (3.7)238 (15)<0.001
      Use of facemask2899 (91.0)1442 (90.3)1457 (91.6)0.22
      Type of facemask
      Use of more than one type of facemask
      Surgical mask2824 (88.6)1407 (88.1)1417 (89.1)0.22
      Cloth Mask66 (2.1)35 (2.2)31 (
      • Jara A
      • Undurraga EA
      • González C
      • Paredes F
      • Fontecilla T
      • Jara G
      • et al.
      Effectiveness of an Inactivated SARS-CoV-2 Vaccine in Chile.
      )
      Respirator84 (2.6)34 (2.1)50 (3.1)
      Social Distancing2261 (70.9)1175 (73.6)1086 (68.3)<0.001
      Exposure to person with similar illness684 (21.5)414 (25.9)270 (17.0)<0.001
      Nature of contact
      Family member (lives with you)326 (47.7)215 (51.9)111 (41.1)<0.001
      Social contact86 (12.6)49 (11.8)37 (13.7)
      Workplace198 (29)90 (21.7)108 (40)
      Other74 (10.8)60 (14.5)14 (5.2)
      Health status of participants at the time of Index test
      Isolating at home3059 (96.0)1565 (98.0)1494 (94.1)<0.001
      Hospitalized41 (1.3)32 (2.0)9 (0.6)
      N/A87 (2.7)0 (0)85 (5.4)
      Pregnant60 (4.6)27 (3.8)33 (4.7)
      Concurrent medical conditions659 (20.7)395 (24.7)264 (16.6)<0.001
      Cancer26 (3.9)18 (4.6)8 (3.0)0.003
      Diabetes261 (39.6)171 (43.3)90 (34.1)
      Immunosuppression17 (2.6)11 (2.8)6 (2.3)
      Cardiovascular334 (50.7)221 (55.9)116 (43.9)
      Respiratory disorders75 (11.4)37 (9.4)39 (14.8)
      Others
      Includes: high cholesterol, thyroid problems, allergies, renal disorders, etc.
      177 (26.9)100 (25.3)76 (28.8)
      Vaccination status
      Vaccinated: one dose of any vaccine received before the index test
      Non-vaccinated1732 (54.3)989 (61.9)743 (46.7)<0.001
      Vaccinated1455 (45.7)608 (38.1)847 (53.3)
      Vaccination category
      Non-vaccinated: never received a vaccine dose or duration between first dose of two-dose vaccine, or one dose of a single-dose regimen and index test was less than 14 days. Partially vaccinated: received one dose of a two-dose vaccine at least 14 days before the index test and had either not received the second dose or less than 14 days had elapsed between the second dose and time of index test. Fully vaccinated: received second dose of a two-dose vaccine or one dose of a single-dose regimen 14 or more days before the index test
      Non-vaccinated1164 (36.5)670 (42.0)494 (31.1)<0.001
      Partially vaccinated568 (17.8)319 (20.0)249 (15.7)
      Fully vaccinated1455 (45.7)608 (38.1)847 (53.3)
      Type of vaccine administered
      mRNA vaccines: Pfizer-BioNTech, Moderna; Inactivated vaccines: Sinopharm, Sinovac; Viral-vector vaccines: Oxford/AstraZeneca, Sputnik-V, CanSinoBIO, Janssen
      n=1455n=608n=847
      RNA16 (1.1)5 (0.8)11 (1.3)0.18
      Inactivated1269 (87.2)537 (88.3)732 (86.4)
      Vector170 (11.7)66 (10.9)104 (12.3)
      Brand of vaccine administeredn=1455n=608n=847
      Pfizer-BioNTech8 (0.5)4 (0.7)4 (0.5)0.05
      Moderna8 (0.5)1 (0.2)7 (0.8)
      Sinopharm896 (61.6)387 (63.7)509 (60.1)
      Sinovac373 (25.6)150 (24.7)223 (26.3)
      Oxford/AstraZeneca6 (0.4)3 (0.5)3 (0.4)
      Sputnik-V33 (2.3)12 (2.0)21 (2.5)
      CanSinoBIO129 (8.9)51 (8.4)78 (9.2)
      Janssen2 (0.1)0 (0)2 (0.1)
      low asterisk Ethnic groups from other parts of Pakistan
      low asterisklow asterisk Use of more than one type of facemask
      low asterisklow asterisklow asterisk Includes: high cholesterol, thyroid problems, allergies, renal disorders, etc.
      Vaccinated: one dose of any vaccine received before the index test
      ᵻᵻ Non-vaccinated: never received a vaccine dose or duration between first dose of two-dose vaccine, or one dose of a single-dose regimen and index test was less than 14 days.Partially vaccinated: received one dose of a two-dose vaccine at least 14 days before the index test and had either not received the second dose or less than 14 days had elapsed between the second dose and time of index test.Fully vaccinated: received second dose of a two-dose vaccine or one dose of a single-dose regimen 14 or more days before the index test
      ᵻᵻᵻ mRNA vaccines: Pfizer-BioNTech, Moderna; Inactivated vaccines: Sinopharm, Sinovac; Viral-vector vaccines: Oxford/AstraZeneca, Sputnik-V, CanSinoBIO, Janssen
      After adjusting for age, gender, healthcare worker status, past COVID-19 infection, use of non-pharmaceutical interventions, diabetes, and hypertension, it was found that two doses of mRNA vaccines conferred the greatest protection (VE: 67·4%; 95% CI: 1·8-89·2%), followed by Sputnik-V (VE: 58·5%; 95% CI: 12·8-80·2%), Sinovac (49·3%; 95% CI: 34·8-60·6%) and Sinopharm (VE: 33·8%; 95% CI: 18·6, 46·1%) (Figure 1), while a single shot of CanSinoBIO was 47·9% effective in preventing symptomatic COVID-19. Among the partially vaccinated participants, VE estimates were lower, 29·8% for the mRNA vaccines, and 31·8% for Oxford/AstraZeneca. One dose of inactivated vaccines was ineffective in providing protection against symptomatic COVID-19 infection (Figure 1).
      Figure 1:
      Figure 1Graph showing VE (95% CI) among fully vaccinated participants
      We found that two doses of inactivated vaccines had lower effectiveness against symptomatic disease (between 34% and 48%) compared with 2 doses of the mRNA vaccine (67%) during the period when the delta variant was in circulation. Overall, these estimates are lower than previous clinical trials (
      • Han B
      • Song Y
      • Li C
      • Yang W
      • Ma Q
      • Jiang Z
      • et al.
      Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy children and adolescents: a double-blind, randomised, controlled, phase 1/2 clinical trial.
      ). This could be because the vaccines may have become less effective as a result of emerging variants.
      We report a widespread use of two inactivated vaccines, Sinopharm and Sinovac, among the study population. We found that a two-dose schedule of Sinovac was around 47% effective at preventing symptomatic infection due to the Delta variant. This is consistent with previous estimates, including a recently published study from Jiangsu, China, which showed the vaccine to be 51% effective against symptomatic infection by the Delta variant (
      • Hu Z
      • Tao B
      • Li Z
      • Song Y
      • Yi C
      • Li J
      • et al.
      Effectiveness of inactivated COVID-19 vaccines against severe illness in B.1.617.2 (Delta) variant-infected patients in Jiangsu, China.
      ). A similar estimate (46.8%) was reported for the Sinovac vaccine against the earlier variants in a test-negative case control study from Brazil 24 (
      • Ranzani OT
      • Hitchings MDT
      • Dorion M
      • D'Agostini TL
      • de Paula RC
      • de Paula OFP
      • et al.
      Effectiveness of the CoronaVac vaccine in older adults during a gamma variant associated epidemic of covid-19 in Brazil: test negative case-control study.
      ), while VE for Sinovac was estimated to be of 67% against symptomatic infection from a cohort study in Chile (
      • Jara A
      • Undurraga EA
      • González C
      • Paredes F
      • Fontecilla T
      • Jara G
      • et al.
      Effectiveness of an Inactivated SARS-CoV-2 Vaccine in Chile.
      ).
      Decline in the effectiveness of different COVID-19 vaccines against later variants has been reported from other studies as well (
      • Zheng C
      • Shao W
      • Chen X
      • Zhang B
      • Wang G
      • Zhang W.
      Real-world effectiveness of COVID-19 vaccines: a literature review and meta-analysis.
      ). Bernal et al. reported effectiveness of two doses of Pfizer-BioNTech vaccine to be 93·7% and 88% against the alpha and Delta variants respectively, while Oxford-AstraZeneca vaccine was 74·5% against the alpha variant but 67% against the Delta variant (
      • Lopez Bernal J
      • Andrews N
      • Gower C
      • Robertson C
      • Stowe J
      • Tessier E
      • et al.
      Effectiveness of the Pfizer-BioNTech and Oxford-AstraZeneca vaccines on covid-19 related symptoms, hospital admissions, and mortality in older adults in England: test negative case-control study.
      ). Nasreen et al. reported a similar decline of the effectiveness of the mRNA vaccines against the Delta variant in Ontario (
      • Chung H
      • He S
      • Nasreen S
      • Sundaram ME
      • Buchan SA
      • Wilson SE
      • et al.
      Effectiveness of BNT162b2 and mRNA-1273 covid-19 vaccines against symptomatic SARS-CoV-2 infection and severe covid-19 outcomes in Ontario, Canada: test negative design study.
      ).
      Our study had a few limitations. Documentary verification of the vaccine status was not available as data were collected through phone calls which could have led to misclassification. We tried minimizing this bias by scheduling follow-up calls so that participants could verify their vaccination date using their vaccine card or certificate. The study participants may not be an ideal representative of the target population as certain groups were excluded based on the presence of risk factors.
      We had access to one of the largest testing facilities in the city and were able to assess the effectiveness across a range of vaccines against the Delta variant. The test negative study design controlled for differences in health-seeking behaviors and validity of the diagnostic tests, as all participants were tested at the same place. In addition, investigator bias was minimized as the lab personnel were blinded to both clinical presentation and vaccination status of the participants.
      In conclusion, inactivated COVID-19 vaccines were moderately effective against symptomatic infection in the adult Pakistani population. The mRNA vaccines had higher effectiveness comparable to that observed in other parts of the world. Our findings support a universal evaluation of all vaccines and consideration of additional doses for those who received inactivated vaccines. As countries implement or consider additional vaccine doses in various risk groups, there may be a need for additional booster doses among those who initially received the inactivated vaccines.

      Ethical statement

      Written consent was obtained from the study participants before their enrollment.

      Author contributions

      IN, SO, FJ, NA, AM, and IY conceptualized and designed the study. NA, AM, KL, and MM worked on developing the methodology. SO, IN, and FJ supervised the research. NA, KL, ZH, and UK were responsible for project administration. ZH and UK contributed to the availability of resources. NA, KL, AMY and MC were involved in the investigation process and curated and verified the data.
      NA, AM, AMY, MC, FK, and FQ performed the formal analysis. NA wrote the original draft and IN, FJ, SS, SO, AM, NA, and IY reviewed and edited it.
      NA and AM directly accessed and verified the underlying data reported in the manuscript. All authors confirm that they had full access to all the data in the study and accept responsibility to submit for publication.

      Data availability

      Deidentified data and data dictionary will be made available by the corresponding author upon request.

      Declaration of Competing Interest

      The authors declare no competing interests.

      Acknowledgments

      The authors are grateful for the diligent efforts of the data collection team: Mr. Aziz Ali, Ms. Hasrat Naz, Ms. Kiran Jabeen, Mr. Majid Hussain, Ms. Poonam Ali Shah, and Ms. Rudaba Rais.
      The authors acknowledge the Aga Khan University Clinical Laboratory, the Department of Family Medicine (AKUH), Mr. Mir Asghar Ali, Mr. Navroz Wasanjee and the research administration team of the Department of Pediatrics and Child Health (AKUH), for their invaluable support and contributions in making this study possible.

      Funding

      This study was funded by the Infectious Diseases Research Laboratory (IDRL) at the Aga Khan University), Pakistan. The funder of the study had no role in study design, data collection, data analysis, data interpretation, manuscript prepared and reviewed.

      Appendix. Supplementary materials

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        Safety and immunogenicity of a bivalent SARS-CoV-2 protein booster vaccine, SCTV01C in adults previously vaccinated with inactivated vaccine: A randomized, double-blind, placebo-controlled phase 1/2 clinical trial.
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        Effectiveness of an Inactivated SARS-CoV-2 Vaccine in Chile.
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        Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant.
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        • Gower C
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