key: cord-0847644-vrahjkir
authors: Voko, Z.; Kiss, Z.; Surjan, G.; Surjan, O.; Barcza, Z.; Wittmann, I.; Molnar, G. A.; Nagy, D.; Muller, V.; Bogos, K.; Nagy, P.; Kenessey, I.; Weber, A.; Polivka, L.; Palosi, M.; Szlavik, J.; Rokszin, G.; Muller, C.; Szekanecz, Z.; Kasler, M.
title: Effectiveness and waning of protection with different SARS-CoV-2 primary and booster vaccines during the Delta pandemic wave in 2021 in Hungary (HUN-VE 3 study)
date: 2022-04-18
journal: nan
DOI: 10.1101/2022.04.14.22273898
sha: 72d301ed25ee4e357c147b21896f79466dba67a3
doc_id: 847644
cord_uid: vrahjkir

Background: In late 2021, the pandemic wave was dominated by the Delta SARS-CoV-2 variant in Hungary. Booster vaccines were offered starting from August 2021. Methods: The nationwide HUN-VE 3 study examined the effectiveness and durability of primary immunization and single booster vaccinations on SARS-CoV-2-related infection, hospitalization and mortality during the Delta wave. Results: The study population included 8,087,988 individuals aged 18-100 years at the beginning of the pandemic. During the Delta wave, after adjusting for age, sex, calendar day, and chronic diseases, vaccine effectiveness (VE) of primary vaccination against registered SARS-CoV-2 infection was between 11% to 77% and 18% to 79% 14-120 days after primary immunization in the 16-64 and 65-100 years age cohort respectively, while it decreased to close to zero in the younger age group and around 40% or somewhat less in the elderly after 6 months for almost all vaccine types. In the population aged 65-100 years, we found high, 88.1%-92.5% adjusted effectiveness against Covid-19 infection after the Pfizer-BioNTech, and 92.2%-95.6% after the Moderna booster dose, while Sinopharm and Janssen booster doses provided 26.5%-75.3% and 72.9%-100.0% adjusted VE, respectively. Adjusted VE against Covid-19 related hospitalization was high within 14-120 days for Pfizer-BioNTech: 76.6%, Moderna: 83.8%, Sputnik-V: 78.3%, AstraZeneca: 73.8%, while modest for Sinopharm: 45.7% and Janssen: 26.4%. The waning of protection against Covid-19 related hospitalization was modest and booster vaccination with mRNA vaccines or the Janssen vaccine increased adjusted VE up to almost 100%, while the Sinopharm booster dose proved to be less effective. VE against Covid-19 related death after primary immunization was high or moderate: for Pfizer-BioNTech: 81.5%, Moderna: 93.2%, Sputnik-V: 100.0%, AstraZeneca: 84.8%, Sinopharm: 58.6%, Janssen: 53.3%). VE against this outcome also showed moderate decline over time, while booster vaccines restored effectiveness up to almost 100%, except for the Sinopharm booster. Conclusions: The HUN-VE 3 study demonstrated waning VE with all vaccine types for all examined outcomes during the Delta wave and confirmed the outstanding benefit of booster vaccination with the mRNA or Janssen vaccines. This is the first study to provide comparable effectiveness results for six different booster types during the Delta pandemic wave.

Introduction 65

In Hungary, six different SARS-CoV-2 vaccines were approved in the first half of 2021, and five of 66 them were investigated and showed high or very high short-term effectiveness against SARS-CoV-2 67 infection (Alpha variant) and Covid-19 related mortality in the nationwide HUN-VE 1 study (1). In 68 the second half of 2021, a growing number of studies started reporting a waning effectiveness for 69 vaccines over time, especially against the new, more infectious Delta variant and to less extent 70

against Covid-19 related death (B.1.617.2) (2,3,4,5,6). To maintain protection against emerging new 71 waves and variants, several European countries including Hungary started offering booster vaccine 72 doses in summer 2021 (7, 8) . The benefit of booster vaccination has been demonstrated by a number 73 of recent studies (9,10,11). On August 1, 2021, the Hungarian government introduced the option of a 74

booster dose with one of six vaccine types at least 4 months after primary immunization, particularly 75

for the vulnerable population such as people aged 60 years or older and those having chronic 76

illnesses (12). 77

The aim of our study was to estimate the effectiveness of six different vaccine types as well as their 78

combinations as primary or booster vaccines against SARS-CoV-2 infection, Covid-19 related 79 hospitalization and death during the Delta pandemic wave between September 2021 and December 80 2021 in Hungary. We also aimed to evaluate the durability of protection offered by vaccine 81 combinations to provide guidance for countries where multiple vaccine types are available. 82

Methods 83

The study population included Hungarian residents aged 18 to 100 years who were registered in the 84

Hungarian-COVID-19 Registry based on the National Public Health Center (NPHC) and National 85

Health Insurance Fund Manager (NHIFM) database on March 4, 2020, when the first case of 19 infection was detected in Hungary. Exclusion criteria included any inconsistencies in data such as 87 a person receiving two different vaccine types for primary immunization, missing information on the 88 type of the second vaccine dose, first vaccination administered before the first potential date of 89 administration, fewer than 14 days between the first and second doses, a date of diagnosis before the 90 first case was officially reported, or a date of death preceding the date of first vaccination. Fewer than 91 1,000 cases were excluded for reasons other than age outside the predefined range. 92

Cases of SARS-CoV-2 infection were reported on a daily basis using a centralized system via the 93 National Public Health Center (NPHC). The report is based on (i) Covid-19-related symptoms 94 identified by hospital physicians and general practitioners, (ii) positive nucleic acid amplification test 95

reported by microbiological laboratories. Cases identified by symptoms were confirmed by PCR or 96 antigen test included in the EC rapid test list (13). Covid-19 related hospitalization was defined as 97 hospitalization with a positive PCR or antigen test within 5 days before or 20 days after admission to 98 hospital. Covid-19 related mortality was defined as death during SARS-CoV-2 positivity without 99 previously declared recovery and without another clear cause of death (e.g., accident, suicide). The 100 definition was based on WHO recommendations and defined by the healthcare government (14) . is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 18, 2022. ; https://doi.org/10.1101 https://doi.org/10. /2022 Vaccine effectiveness during Delta wave 4 Vaccine effectiveness (VE) was defined as 1 minus the incidence rate ratio of the outcome in 108 question . Vaccine combinations administered to at least 3,000 people by December 31, 2021 or with  109  at least 300 cases from the start of the pandemic until December 31, 2021 in Hungary were included  110 in the analysis. Vaccine combinations were further broken down into subcategories according to the 111 time elapsed since their administration. These subcategories were defined as 14-120, 121-180, 181-112 240, or Age was categorized as 18-24, 25-34, 35-44, 45-54, 55-64, 65-74, 75-84, and 85-100 and calendar day (modelled as a random effect), which is better suited for over-dispersed count data 140 than the traditional Poisson regression. The model is a random intercept model, which allows for 141 different incidence rates in the reference category (i.e., unvaccinated) each day, but assumes fixed 142 effect of the intervention categories. Separate models were fitted to estimate age group specific 143 effects (i.e., 18-64 years and 65-100 years). 144

The study was approved by the Central Ethical Committee of Hungary (OGYÉI/10296-1/2022 and 145 IV/1722-1/2022/EKU). 146

Results 147

The study population included 8,087,988 individuals (18-64 years: n=6,193,552, 65-100 years: 148 n=1,894,436) at the beginning of the pandemic. 149 . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 18, 2022. ; https://doi.org/10.1101 https://doi.org/10. /2022 In the age group of 16-64 years, the crude incidence rate of SARS-CoV-2 infection was 67.6 per 150 100,000 person-days in the unvaccinated cohort during the Delta wave. In the primary vaccination 151

cohorts, crude incidence rates varied between 5.2 and 38.3 per 100,000 person-days after 14-120 152 days of the second vaccine dose (Supplementary Table 2 ). Crude incidence rates of infection 153 progressively increased 120-180, 181-240 and >240 days after the second vaccine dose for each 154 vaccine type, even exceeding crude incidence rates of the unvaccinated population 6 months after 155 primary vaccination. On the other hand, after booster vaccination with the Pfizer-BioNTech, 156

Moderna or Janssen vaccines, crude incidence rates fell below 20 per 100,000 person-days, 157

regardless of the type of vaccines used for primary immunization except for the Sputnik-V, Sputnik-158 V, Janssen combination. On the other hand, booster vaccination with the Sinopharm vaccine resulted 159 in crude incidence rates of 25.2-61.2 per 100,000 person-days, depending on the type of the primary 160 vaccination (Supplementary Table 2 ). 161

Similar results were seen in the 65-100 years age cohort: lower crude incidence rates of SARS-CoV-162 2 infection 14-120 days after primary vaccination for each vaccine type compared to the 163 unvaccinated cohort (54.8 per 100,000 person-days), increasing infection rates after 4 months, and 164 very low rates (<10 per 100,000 person-days) after booster vaccination with mRNA vaccines, 165 regardless of primary vaccine types (Supplementary Table 3 ). 166

Higher effectiveness and slightly less waning of protection were found against Covid-19 related 167 hospitalization and death in both age groups. However, both hospitalization and mortality rates were 168 close to respective rates in the unvaccinated cohort 240 days after the second vaccine dose for most 169 vaccine types, while booster vaccination led to relevant decreases in the incidence rates of these 170 outcomes (Supplementary Tables 4-7) . 171

After adjusting for age, sex, chronic diseases, and calendar day, vaccine effectiveness of primary 172 vaccination against SARS-CoV-2 infection varied between 10.9% and 76.9% 14-120 days after the 173 second dose in the 16-64 years age cohort ( Figure 1A ), and between 17.8% and 79.1% in the 65-100 174 years age cohort ( Figure 2A ). Adjusted vaccine effectiveness decreased to close to zero in the 175 younger age group and around 40% or somewhat less in the elderly after 6 months for almost all 176 vaccine types. In the population aged 65-100 years, we found high, 88.1%-92.5% adjusted 177 effectiveness against Covid-19 infection after the Pfizer-BioNTech booster dose, and 92.2%-95.6% 178 adjusted effectiveness after the Moderna booster during the first 4 months after booster 179

immunization. The Sinopharm and Janssen boosters provided 26.5%-75.3% and 72.9%-100.00% 180 adjusted effectiveness, respectively, depending on primary immunization type ( Figure 1A and 2A, 181

Supplementary . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 18, 2022. The lower effectiveness of globally available vaccine types against the Delta variant compared to 214

Alpha has been widely reported (15, 15, 17, 18, 19) . Our study is among the first to report effectiveness 215 data for the Sinopharm, Sputnik-V, and Janssen vaccines against the Delta variant, showing a lower 216 benefit for Janssen and Sinopharm compared to other vaccine types. 217

Most vaccine types provided sustained protection and high effectiveness against Covid-19 related 218 death and hospitalization even after only two doses, which is in line with previous publications 219 (20, 21) . A recent prospective study from the United States reported similar, 85% effectiveness of 220 mRNA vaccines against Covid-19 related hospitalization among patients infected with the Delta or 221

Alpha SARS-CoV-2 variant after two doses (20). In a study conducted in the United Arab Emirates 222 (UAE), the Sinopharm and Pfizer-BioNTech vaccines provided 95% and 98% effectiveness against 223

Covid-19 related hospitalization in patients infected with the Delta variant, respectively (22). We 224 found high protection against mortality of Pfizer-BioNTech, Moderna, Sputnik-V, and AstraZeneca 225 vaccines but lower than 60% effectiveness for the Janssen and Sinopharm vaccines during the Delta 226 wave in these age groups. 227

Waning effectiveness was observed for all outcomes, mostly for protection against SARS-CoV-2 228 infection, especially 6 months after primary immunization. The waning of vaccine effectiveness after 229 primary immunization is widely discussed (23,24), and in most cases it is attributed to the time-230 dependent decrease of neutralizing response against the SARS-CoV-2 virus. However, most studies 231 have reported maintained and only slightly decreased protection against severe outcomes (4,5,6,25). 232

There have been very few comparative studies on Sinopharm and other vaccines. The Pfizer vaccine 233 was found to be superior to Sinopharm with respect to post-vaccination quantitative antibody titers 234 (26) . Similarly, the Sputnik V vaccine was also more immunogenic compared to Sinopharm (27). 235

Regarding the Omicron variant, both Sinopharm and Janssen yielded significantly lower neutralizing 236 . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 18, 2022. ; https://doi.org/10.1101/2022.04.14.22273898 doi: medRxiv preprint activities compared to Pfizer and Moderna, (28) and, this may explain that in our study, these 237

vaccines showed a steeper decrease in efficacy over time. 238

Improved protection against all Covid-19 related outcomes with booster vaccines compared to 239 primary immunization has been demonstrated by a number of studies (9,10,11 Although few people received Janssen booster vaccine, we were still able to examine its 276 effectiveness. It proved to be highly effective against SARS-CoV-2 infection as well as against 277

Covid-19 related hospitalization and death, with similar protection to mRNA boosters irrespective of 278 the type of the primary vaccination. Because only few people received AstraZeneca or Sputnik-V 279 boosters in our study, we were not able to assess the effectiveness of these combinations. 280 . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 18, 2022. ; https://doi.org/10.1101/2022.04.14.22273898 doi: medRxiv preprint Vaccine effectiveness during Delta wave 8 The strengths of our study include its nationwide nature inclusion of six different vaccines as primary 281 or booster immunization, the robust number of more than 6 million vaccinated individuals, the 4 282 different time frames for the evaluation of waning effectiveness after primary vaccination, the 3 283 different outcomes, and the adjustment for the history of chronic diseases. 284 However, despite adjustments for age, sex, calendar day, and chronic diseases, further important 285 covariates such as medications or socio-economic status were not included in the analysis. The latter 286 could be related to differences in the likelihood of seeking SARS-CoV-2 testing, chance of detection, 287 uptake of vaccines, prognosis of Covid-19, thus may also have resulted in residual confounding. 288

Furthermore, the diagnosis of SARS-CoV-2 infection could also be established based on clinical 289 symptoms, which might have resulted in differential misclassification, somewhat overestimating 290 vaccine efficacy because physicians might have been less likely to diagnose Covid-19 in vaccinated 291

individuals. On the other hand, misclassification might have biased the results in the other direction 292 (i.e., underestimation of vaccine efficacy), as well, regarding the first infection as outcome, as the 293

proportion of unregistered cases were likely to be higher among the unvaccinated population due to 294 the higher incidence among them. Because of the issue of unregistered cases, we did not censor 295 patients with registered infection in the analysis of the risk of hospitalization and death. As the 296 proportion of individuals with natural immunity were likely to be higher in the unvaccinated 297 population, our estimates can be considered conservative in respect of hospitalization and death. . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 18, 2022. ; https://doi.org/10.1101/2022.04.14.22273898 doi: medRxiv preprint Kaleeckal, A. H., Latif, A. N., Shaik, R. M., Abdul Rahim, H. F., Nasrallah, G. K., Al Kuwari, M. 324 G . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 18, 2022. ; https://doi.org/10.1101 https://doi.org/10. /2022 

Fiolet, T., Kherabi, Y., MacDonald, C. J., Ghosn, J., & Peiffer-Smadja, N. (2022) . Comparing 397 COVID-19 vaccines for their characteristics, efficacy and effectiveness against SARS-CoV-2 and 398 variants of concern: a narrative review. . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 18, 2022. ; https://doi.org/10.1101 Lopez Bernal, J. (2022 The authors would like to thank Richárd Kiss for the initial data curation and dataset validation. 483 . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) A  d  j  u  s  t  e  d  v  a  c  c  i  n  e  e  f  f  e  c  t  i  v  e  n  e  s  s  a  g  a  i  n  s  t  r  e  g  i  s  t  e  r  e  d  S  A  R  S  -C  o  V  -2  i  n  f  e  c  t  i  o  n  ,  C  o  v  i  d  -1  9  r  e  l  a  t  e  d   485   h  o  s  p  i  t  a  l  i  z  a  t  i  o  n  a  n  d  d  e  a  t  h  d  u  r  i  n  g  t  h  e  D  e  l  t  a  w  a  v  e  i  n  t  h  e  H  u  n  g  a  r  i  a  n  p  o  p  u  l  a  t  i  o  n  a  g  e  d  1  6  -6 The datasets generated for this study can be found in the MedRxiv repository. Further inquiries can 494 be directed to the corresponding author. 495

Vaccines became the cornerstone of defense against Covid-19, especially as lockdown measures 497 needed to be eased. In a previous study (HUN-VE 1) we investigated vaccine efficacy of five 498 different vaccines (mRNA-based, subunit-based and inactivated virus-based vaccines) during the 499 alpha wave. In the present paper, we analyze vaccine effectiveness (in terms of infection, 500

hospitalization, and mortality) in primary immunized and first boostered groups of cases during the 501 delta wave using nationwide data from Hungary related to six vaccine types (Pfizer-BioNTech, 502

Moderna, Sputnik-V, AstraZeneca, Sinopharm and in this paper also the Janssen vaccine). We show 503 waning of the protection over time with all vaccines used for primary vaccination. Different 504 combination of primary vaccinations and boosters were effective in a different manner (with 505

Sinopharm and Janssen vaccines somewhat less effective in most aspects). Overall, most boosters 506 restored vaccine effectiveness to nearly 100% in case of Covid-related hospitalization and Covid-507 related mortality. The strengths of our study are, that it provides nationwide data, it enables 508 comparison of primary vaccinated vs. boostered groups, and that it enables comparison of six 509 different vaccine types. Furthermore, cases with age < 65 or >65 years could be separately analyzed, 510

providing data on vaccine effectiveness in the elderly. 511 . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 18, 2022. ; https://doi.org/10.1101/2022.04.14.22273898 doi: medRxiv preprint . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 18, 2022. ; https://doi.org/10.1101/2022.04.14.22273898 doi: medRxiv preprint . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 18, 2022. ; https://doi.org/10.1101/2022.04.14.22273898 doi: medRxiv preprint

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