key: cord-0993736-vyc1kt8p
authors: Abarca, K.; Iturriaga, C.; Urzua, M.; Le Corre, N.; Pineda, A.; Fernandez, C.; Dominguez, A.; Gonzalez, P. A.; Bueno, S. M.; Donato, P.; Espinoza, P.; Fuentes, D.; Gonzalez, M.; Guzman, P.; Munoz, P.; Perez, C. M.; Potin, M.; Rojas, A.; Gonzalez-Aramundiz, J. V.; Galvez, N. M. S.; Kalergis, A. M.
title: Safety and efficacy of two immunization schedules with an inactivated SARS-CoV-2 vaccine in adults. A randomized non-inferiority clinical trial.
date: 2022-02-08
journal: nan
DOI: 10.1101/2022.02.07.22270215
sha: d3f51f37d40df7f01cc47aa2e7a694380fdd61de
doc_id: 993736
cord_uid: vyc1kt8p

Background: Several vaccines have been developed to control the COVID-19 pandemic. CoronaVac (Sinovac Life Sciences), an inactivated SARS-CoV-2 vaccine, has demonstrated safety and immunogenicity in previous studies, preventing severe COVID-19 cases. We further investigated the safety and efficacy of two immunization schedules of CoronaVac in a non-inferiority trial in healthy adults. Methods: This is a multi-center and randomized clinical trial. Healthy adults were enrolled at eight centers in Chile. Participants were randomly assigned to two vaccination schedules, receiving two doses with either 14 (0-14) or 28 (0-28) days between each. 2302 participants were vaccinated. The primary safety and efficacy endpoints were solicited adverse events (AE) within 7 days after each dose and compared the number of cases of SARS-CoV-2 infection 14 days after the second dose between schedules, respectively. Findings: The most frequent local AE was pain at the injection site, which was less frequent in participants aged over 60 years. Other local AEs were reported in less than 5% of participants. The most frequent systemic AEs were headache, fatigue, and myalgia. The remaining AEs were minor allergic reactions and fever. Most AEs were mild and transient. There were no significant differences for local and systemic AE between schedules. No anaphylactic reactions or vaccine-related severe AEs were observed. 58 COVID-19 cases were confirmed, and all but two of them were mild. No differences were observed in protection between schedules. Interpretation: CoronaVac is safe, especially in over 60 years-old participants. Both schedules protected against COVID-19 hospitalizations. Funding: MINSAL, Chile, CPC & IMII, Chile.

In March 2020, the COVID-19 pandemic, a disease caused by the severe acute 91 respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared 1 . Two years into this 92 pandemic, more than 250 million cases have been diagnosed worldwide, and more than 93 5 million deaths can be related to COVID-19 2 . In Chile, since March 2020, 1.7 million 94 laboratory-confirmed cases have been reported, and more than 38,000 deaths can be 95 related to COVID-19 by December 2021 3 . 96 Initial COVID-19 outbreaks exhibited high morbidity and mortality in individuals over 60 97 years of age or with comorbidities, such as obesity, chronic pulmonary disease, cardiac 98 disease, and immunosuppressed population 4,5 . Antiviral drugs or immunomodulators 99 have not been a successful treatment 6 . Prophylactic strategies with drugs, such as 100 hydroxychloroquine or ivermectin did not show any significant reduction in the risk of 101 SARS-CoV-2 infection 7 . Other treatments, such as post-exposure type I interferon 102 prophylaxis, are still being evaluated 8 . 103 Vaccination is an essential prophylactic strategy to prevent pathogen spreading and the 104 disease caused by a viral infection 9 . Early during the pandemic, the development of 105 vaccines against SARS-CoV-2 was vigorously pursued. Different vaccine platforms 106 were generated to prevent COVID-19, such as mRNA vaccines or viral vector-based 107 vaccines 10 . Among these, CoronaVac ® is an inactivated vaccine against SARS-CoV-2 108 developed in Vero cells (Sinovac Life Sciences, Beijing, China). Preclinical studies 109 performed in mice, rats, and non-human primates demonstrated that this vaccine was 110 immunogenic and induced anti-SARS-CoV-2 neutralizing antibodies 11 . Moreover, 111 partial or complete protection against pneumonia after a viral challenge was shown in 112 . CC-BY-NC-ND 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 February 8, 2022. ; https://doi.org/10.1101/2022.02.07.22270215 doi: medRxiv preprint primates 11 . All these results led to human clinical trials. A phase I/II sequential clinical 113 trial was performed, including 144 and 600 healthy adults aged 18 to 59 years, 114 respectively 12 . Two doses (3 and 6 µg) and two vaccination schedules (two doses 115 separated by either two or four weeks) were evaluated. Results demonstrated that this 116 inactivated vaccine was well tolerated with mild local adverse events after two doses 12 . 117 Although anti-SARS-CoV-2 neutralizing antibodies geometric mean titers (GMT) were 118 lower when compared to convalescent patients, the vaccine induced a significant 119 humoral response with both doses and schedules. A phase1/2 sequential clinical trial 120 performed in healthy adults aged 60 years and older showed that CoronaVac ® was safe 121 and well-tolerated in this particular population 13 . Moreover, the 3 µg dose in the elderly 122 group induced anti-SARS-CoV-2 neutralizing antibodies titers similar to those observed 123 in adults aged 18-59 years. All these findings led to the emergency use of CoronaVac ® 124 in China and supported the development of a phase 3 study to evaluate the efficacy of 125 this inactivated vaccine 14 . 126 Due to the availability of CoronaVac ® to the general public in Chile since January 2021, 127 we adapted the initial placebo-controlled phase 3 clinical trial in adults to a non-128 inferiority clinical trial of two different immunization schedules, with the second dose 129 administered either two (0-14) or four (0-28) weeks after the first one, with a planned 12 130 months of follow-up. This report includes the safety and efficacy of non-inferiority results 131 acquired up to six months after the first dose. 132 . CC-BY-NC-ND 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 primary safety endpoint was to evaluate the frequency of AE occurring on the first 7 157 days after each dose of the vaccine in each vaccination schedule. The secondary 158 endpoint was to determine the occurrence of SAE and events of special interest in both 159 vaccination schedules during all the study. 160 The primary non-inferiority efficacy endpoint was to evaluate and compare the 161 protection against confirmed SARS-CoV-2 infection of two vaccination schedules, 162 starting two weeks after the second dose. Non-inferiority of 0-14 over 0-28 schedule 163 was defined as a difference in the protection rate within a threshold of 15%. Secondary 164 efficacy endpoints were to compare both vaccination schedules regarding hospitalized 165 cases and deaths within the same period. Fisher's exact test; differences in means were tested using Student's t-test; significance 221 level was set at a more rigorous level of 0.01. The percentage of subjects that 222 presented each solicited AE within the first 7 days was obtained for each schedule. The 223 length of the event was presented as median and quantiles 10 and 90. Incidence of 224 . CC-BY-NC-ND 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 February 8, 2022. ; https://doi.org/10.1101/2022.02.07.22270215 doi: medRxiv preprint immediate and non-immediate AE was registered. The number of simultaneous non- 225 immediate AEs were expressed as the sum of different AE and are shown as frequency 226 and percentage by dose and schedule. Differences in the incidence of each AE by age 227 were evaluated using Chi-square or Fisher´s exact test. The COVID-19 incidence, 228 including only cases occurring 14 days after the second dose, was determined for each 229 schedule and subgroups defined by sociodemographic or clinical characteristics. 230 COVID-19-free survival was estimated using Kaplan-Meier analysis, and schedule 231 curve differences were assessed using the Log Rank test. Cox's regression was used to 232 obtain age and gender-adjusted incidence rate ratios and their 95% confidence interval 233 (CI). The proportional hazards assumption was met. For safety and efficacy, we looked 234 at the non-inferiority of the 0-14 schedule over the 0-28 schedule, with a margin of 15%. Table 3) . 281 After each dose, the most frequent solicited systemic AEs were headache, fatigue, and 282 myalgia, reported in 20-26%, 12-17%, and 11-14% of the participants, respectively. The 283 remaining systemic AEs were reported in less than 10% of the vaccinated participants. 284 Notably, minor allergic reactions and fever were reported by less than 2% and 1% of the Table 6 ).

. CC-BY-NC-ND 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 February 8, 2022. ; https://doi.org/10.1101/2022.02.07.22270215 doi: medRxiv preprint

The incidence of COVID-19 cases tends to be higher in health care workers compared 336 with the general population for both immunization schedules (for 0-14 schedule, cases 337 presented in 4.5 v/s 2.4% and for 0-28 in 3.1 v/s 1.7%); but these differences were not 338 statistically significant. Also, the infection rate tends to be lower in ≥ 60 years old 339 participants, but the significance level set for this analysis was not achieved (p=0.024). 340 No statistical differences were observed in the frequency of COVID-19 cases between 341 sex and comorbidities. 342 . CC-BY-NC-ND 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 February 8, 2022. This non-inferiority trial demonstrated that the virus inactivated, CoronaVac ® , given in 344 two doses, with a 14 or 28 days interval between each dose, was safe, well-tolerated, 345 and protective. A six-month surveillance showed a non-inferiority of the 0-14 over the 0- 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 February 8, 2022. ; https://doi.org/10.1101/2022.02.07.22270215 doi: medRxiv preprint ≥ 60 years old, and 45% had chronic conditions. Lower frequencies of post-vaccination 367 AEs were observed for the older age cohort compared to the younger participants. 368 Consistently with this notion, only one elderly subject developed a fever after 369 vaccination, a condition that could escalate in older people. Concordantly, in a 370 nationwide cross-sectional study for side effects of CoronaVac ® performed in Turkey, CC-BY-NC-ND 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 February 8, 2022. ; https://doi.org/10.1101/2022.02.07.22270215 doi: medRxiv preprint decisions for massive immunization against COVID-19. A more rapid schedule could 389 lead to faster vaccination of the population, which could be relevant during an epidemic. 390 It is essential to evaluate differences regarding immunogenicity, efficacy, and 391 effectiveness between an accelerated schedule versus a standard four-week interval. 392 Two previous reports with this vaccine showed a more robust immune response for the 393 0-28 schedule than for the 0-14 schedule 12 . A phase I/II trial held in China showed 394 higher neutralizing antibodies seroconversion rates for the 0-28 schedule compared to 395 the 0-14 schedule 12 . 396 Regarding efficacy, although we observed a trend toward higher efficacy for the 0-28 397 schedule compared to the 0-14 schedule, these differences were not statistically 398 significant. A previous study that evaluated the efficacy of CoronaVac ® in a 0-14 399 schedule demonstrated that this parameter was higher in participants who received the 400 two doses with an interval of over 21 days 25 . An explanation for this apparent 401 discrepancy is that in our study, the group included in the 0-14 schedule consisted 402 mainly of healthcare workers, which are usually more exposed to the virus and therefore 403 have higher risks of infection. Further studies with a more homogeneous population 404 could contribute to addressing these questions. 405 Older age is a described risk factor related to COVID-19 severity 30 , also observed in 406 our study. Here, the two severe cases reported occurred just in older participants. 407 However, the frequency of cases tended to be lower in this age group. This could be X-axis shows days elapsed from the second dose to the event or censoring time. 558 Censoring was set at the date of the third vaccination, retirement from the study, or 559 reaching six months after the second dose, whichever occurred first. 560 561 . CC-BY-NC-ND 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 February 8, 2022. . CC-BY-NC-ND 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 February 8, 2022. ; https://doi.org/10.1101/2022.02.07.22270215 doi: medRxiv preprint Data are presented as frequency and percentage of the total number of cases in each subgroup and were compared with Chi-square test or Fisher exact test; all p values were higher than 0.05.

. CC-BY-NC-ND 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 February 8, 2022. ; https://doi.org/10.1101/2022.02.07.22270215 doi: medRxiv preprint

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