4 дозы против омикрона

chuka_lis — 17.02.2022 Израильтяне первыми начали делать бустерные прививки (3 доза) и повторные бустерные прививки (4 доза), как только случаи ковида пошли в рост. Так что они первые и докладываются о результатах. В исследовании проверена эффективность 4 доз мРНК вакцины (BNT162b2, 154 человека, или mRNA1273, 120 человек) против омикрона.
Волонтерами были медработники, которые получили 3 дозы, и титр антител в крови которых был на уровне равно или менее 700 BAU примерно у половины, до получения 4 прививки. Контролем была группа из 426 человек, примерно совпадающая по возрасту, у которых были 3 дозы вакцины (последняя не более чем 4 месяца тому) и похожие титры антител.
Вообще же, за прошедшие 4-5 месяцев с момента 3 прививки, титр антител к РСЧ у всех упал в 6 раз, по сравнению с тем как он подрос вскорости после нее. Но все равно это было в 5 раз выше, чем титр перед 3 дозой (которая была сделана, всреднем, через 5 месяцев после 2й). У всех, кроме 2 человек, перед 4 дозой, титры антител были выше порога определения. Среднегеометрический нейтрализующий титр (GMT) был для файзера - 355 (95%CI 270-467), и 276 (95%CI 210-363) для модерны.
После 4 прививки9 через 2 недели), в опытной группе, титр антител увеличился почти в 10 раз (стал, в среднем, 3788 IU для файзера и 5192 IU для модерны), а нейтрализующая активность против омикрона была в 8 раз выше, чем было до 4 прививки. Так что в этот период после 4 дозы, иммунитет волонтеров вышел примерно на тот же уровень, на котором он был после 3 бустерной дозы. У контроля, не получивших 4 прививку, титр антител продолжал прогрессивно снижаться за время исследования (длившегося около полутора месяцев, начиная с конца декабря 2021).
Касательно Т-клеточного ответа, 4 доза его не особо поменяла, за эти же 2 недели (как гуморальный): он вырос с 50% реакции в группе файзера, до 60% , и с 60%, до 80% для модерны, при этом количество реагирующих клеток в крови- не изменилось для файзера и подросло в 2.5 раза для модерны..
Тем не менее, не сморя на улучшившиеся характеристики иммунного овтета, заболеваемость ковидом в группе привитых была частая. Преимущественно, с умеренной симптоматикой, и, что важно, с выделением высоких уровней коронавируса (у всех заболевших, что в опыте, что в контроле (они ж все привитые 3-4 дозами) - для определения коронавируса надо было 24-25 циков ПЦР, в среднем..
Сравнивали, конечно, не с непривитыми, а с теми кто имел 3 дозы. Среди тех, кто получил 3 дозы, заболело ковидом примерно 17% (73 из 426), а среди тех, кто был привит 4 дозами- около 18-20%, (28 из 154 для файзера, 24 из 120 для модерны).
Для всех групп, примерно у 70% ковида случаев температура не была выше 38С, и, в основном, температурили пару дней. Среди всех пробоев (133), 19 случаев были асимптоматичными в течении первых 7 дней после первого положительного ПЦР.
Согласно данным авторов, эффективность 4 доз вакцины против омикрона для файзера составила 30%, а для модерны- 11%.
Касательно симптоматичного ковида, то защитная эффективность была выше: 43% для файзера и 31% для модерны.
После 4 привики, в группе получивших ее, 80% сообщили о локальных осложнениях, и 45% об общих (43% для файзера и 56% для модерны). Наиболее частые общие реакции на првивку были слабость, миалгии и головная боль. Среди осложнения не было тяжелых, никто не нуждался в госпитализации. Температура выше 37.5С была только у 7%. Большинство побочек были умеренные, в и среднем, проходили за пару дней (1.7 суток). У тех, кто моложе, побочки от прививки были чаще. Вобщем, 4 доза переносилась примерно как и 3я.
Выводы авторов: для того чтобы предотвращать заболеваемость ковидом от омикрона и подобных ему штаммов, и предотвращения распространеняи вируса, нужна вакцина следующего поколения, более специфичная к штамму, чем имеющаяся.
Following the emergence of the Omicron variant of concern, we investigated immunogenicity, efficacy and safety of BNT162b2 or mRNA1273 fourth dose in an open-label, clinical intervention trial. METHODS Primary end-points were safety and immunogenicity and secondary end-points were vaccine efficacy in preventing SARS-CoV-2 infections and COVID-19 symptomatic disease. The two intervention arms were compared to a matched control group. Eligible participants were healthcare-workers (HCW) vaccinated with three BNT162b2 doses, and whose IgG antibody levels were ≤700 BAU (40-percentile). IgG and neutralizing titers, direct neutralization of live VOCs, and T-cell activation were assessed. All participants were actively screened for SARS-CoV-2 infections on a weekly basis. RESULTS Of 1050 eligible HCW, 154 and 120 were enrolled to receive BNT162b2 and mRNA1273, respectively, and compared to 426 age-matched controls. Recipients of both vaccine types had a ~9-10-fold increase in IgG and neutralizing titers within 2 weeks of vaccination and an 8-fold increase in live Omicron VOC neutralization, restoring titers to those measured after the third vaccine dose. Breakthrough infections were common, mostly very mild, yet, with high viral loads. Vaccine efficacy against infection was 30% (95%CI:-9% to 55%) and 11% (95%CI:-43% to +43%) for BNT162b2 and mRNA1273, respectively. Local and systemic adverse reactions were reported in 80% and 40%, respectively. CONCLUSIONS The fourth COVID-19 mRNA dose restores antibody titers to peak post-third dose titers. Low efficacy in preventing mild or asymptomatic Omicron infections and the infectious potential of breakthrough cases raise the urgency of next generation vaccine development.

RESULTS Participants: Of a total of 6,597 HCW enrolled to the Sheba HCW COVID Cohort since 2020, 1050 were eligible to participate (Figure 1). Of these, 154 were enrolled to the BNT162b2 arm on December 27-28, 2021. One week later, on January 5-6, 2022, after the second arm was approved, 120 participants were enrolled to the mRNA1273 arm. From the remaining eligible 776 participants, controls were age matched in a 2:1 ratio to participants in each arm. Participants in the BNT162b2 arm were slightly older than those in the mRNA1273 arm (58.9±13.3, vs. 55.1±12.5). Baseline characteristics of the study trial population on enrollment is described in Table S3. On January 3, 2022, the Israeli MOH approved a fourth vaccine to any adult older than 60, and to all HCW. Thus, from the Control group of 426, during the study period 181 received the fourth vaccine out of the study, and after vaccination were censored and contributed no further information to our analyses. Fourth dose Safety: No immediate responses were recorded. All 274 participants in both BNT162b2 and mRNA1273 arms replied to the adverse event questionnaire sent on day 5, 7, 14 and 21. No serious adverse events were reported. No hospital admissions were reported. The only unsolicited events reported were ocular redness and pain by two participants who were referred to the ophthalmology emergency room, where they were examined and diagnosed with conjunctivitis, unrelated to vaccination. Solicited local adverse events (AE) were common, reported by 121 (78.6%, 95%CL: 71.2-84.8%) of BNT162b2 recipients vs. 99 (82.5%, 95%CL 74.5-88.8%) of mRNA1273 recipients. Among BNT162b2 recipients, local AE were more often reported by younger participants (88% 95%CL 80.6-95.3% compared with 69.6%, 95%CL 59.4-79.7% in >60 years of age). This difference was minor among mRNA1273 recipients. Most AE were reported as mild, and resolved within 1.7 days (Figure 2, Table S4). Solicited systemic adverse events were reported by 42.9% (95%CL 35-50.7%) of BNT162b2 recipients and 55.8% (95%CL 46.9%-64.7%) of mRNA1273 recipients. Younger participants reported systemic AE more commonly than older participants for each of the AEs and in both vaccines, but this effect was small and did not reach statistical significance. Systemic adverse events resolved within 1.3 days ± 2.42. The most common adverse event reported was fatigue (27.3%, 95%CL 20.4-35.0% in BNT162b2 and 40.8%, 95%CL 31.9-49.6% in mRNA1273), followed by myalgia and headache. Fever was relatively uncommon, with only 7.1% (95%CL 3.1-11.2%), reported fever above 37.5oC, and slightly less in mRNA1273 recipients. Fever resolved within 24-36h in either group (Figure 2, Table S4). Immunogenicity: Five months after receipt of the third dose (pre-dose 4) anti-RBD IgG titers were 6- fold lower than one month after receiving the third dose (peak post-dose-3 titers) in all three groups. Yet, they were 5 fold higher than titers measured five months after the second dose (pre-dose 3). Within 1-3 weeks of administration of either of the vaccines' fourth dose, anti-RBD IgG titers increased 9-10-fold, to titers slightly higher than those of the first month after the third dose (Table S5 and Figure 3). At the same time, anti-RBD-IgG levels of the control group continued to wane (IgG GMT level of 340, 95%CI: 303-381). All but two cases of pre-dose-4 neutralizing antibody titers (4-5 months after the third dose) were above the limit of detection, with a GMT of 355 (95%CI 270-467) and 276 (95%CI 210-363) for BNT162b2 and mRNA1273, respectively. At this time point, they were 7-9-fold lower than at their peak after the third dose. Yet, they were 5-6-fold higher than at their pre-dose-3 time point (five months after the second dose). Within two weeks of administration of the fourth dose a peak level was observed, reaching 3788 IU and 5192 IU for BNT162b2 and mRNA1273, respectively (Table S5, Figures 3c and d). T cell response: In total, 58 and 56 recipients of BNT162b2 and mRNA1273, respectively, were assessed for T-cell activation on day 1, before receiving the fourth dose. Among BNT162b2 recipients, 53 of the 56 were re-assessed on day 14. The proportion of responders increased from 50% to 60%, yet, the mean number of T cells activated by the spike protein did not change (131±27 to 132±32). Among mRNA1273 recipients, 40 of the 56 were re-assessed on day 14. The proportion of responders increased from 61% to 87% and the average IFNγ activated T cells increased from 72±13 to 203±36 (Table S5, Figure 3e-3f). Direct neutralization of Omicron compared to other strains: Samples of 25 randomly picked participants in each group were assessed for direct neutralization of Omicron VOC compared to Delta VOC and Wu-1 strain before the fourth dose (4-5 months after the third dose), and 7 and 14 days after. For both vaccines, and at all time-points, neutralization of Omicron was approximately 10-fold less than that of Wu-1 and 4-7 folds lower than Delta. BNT162b2 recipients demonstrated increased neutralization of Omicron VOC by 8.5-fold, one week after administration of the fourth dose, with an additional non-significant increase during the second week, reaching a 10.7-fold increase by day 14. mRNA1273 recipients demonstrated a 7-fold increase within one week that did not increase much further by day 14 (total 7.2-fold increase). Among BNT162b2 recipients Delta neutralization increased by 11-fold within one week, with no further increase observed at 14 days. While a 10.1-fold increase was observed for mRNA1273 recipients within 1 week, that further increased to 15.6-fold by day 14 (Figure 4a and 4b). Cumulative Incidence and Vaccine Efficacy In total, 29 and 28 of BNT162b2 and mRNA1273 recipients, respectively, were infected by SARS-CoV-2 during the study period; of these, 28 and 24 were defined as breakthrough infections (i.e., from day 8 after the fourth dose), and 22 and 17 were defined as breakthrough symptomatic disease. Of the 426 participants in the control group, 308 served as matched controls for BNT162b2 recipients and 239 as matched controls of mRNA1273 recipients (54 served as controls for both groups). Of the 426 controls, 181 were censored at some point, since they received a fourth vaccine dose that was approved for HCW on Jan 2, 2022. A total of 79 of the included controls were infected during the full period, but only 73 cases that occurred after day 8 of the study period (between Jan 5, 2022, or Jan 13, 2022, for BNT162b2 and mRNA1273 respectively, until Jan 30, 2022) were included in the analysis. Of all breakthrough infections, 19 were totally asymptomatic during the 7-day follow-up since their first positive SARS-CoV-2 result. In the majority of cases (65-72% in both groups) symptoms were mild (without fever of ≥38oC). Reports of fever that lasted less than 48hr was uncommon, and no fourth dose vaccine recipients reported fever that lasted for >48h. However, 19% of the BNT162b2 control group and 9% of the mRNA1273 control group reported fever that lasted >48 hours (Table 1). While symptoms, in all groups, were mostly mild to negligible, the vast majority had a relatively high viral load (with GMT of N-gene Ct of 25.3 (95%CI: 22.8-28.1), 25.1 (95%CI: 22.1-28.5) and 24.8 (23-26) in the BNT162b2, mRNA1273 and control groups, respectively) and thus, breakthrough cases were presumably infective. (Table 1) The cumulative incidence over the period from 8 days after receipt of BNT162b2 until the end of study (maximum follow up of 29 days) was 18.3% (95% CI: 11.9 to 24.2%), compared to 25.3% (95% CI: 18.5 to 31.5%) among their controls. The cumulative incidence over the period from day 8 to 23 days after receipt of the mRNA1273 vaccine was 20.7% (95% CI: 11.3 to 27.8%), compared to 25.6% (95% CI: 18.0 to 32.5%) among the mRNA1273 controls. (Note that the period of exposure for those receiving mRNA1273 was later and with a higher background incidence than for those receiving BNT162b2, so the cumulative incidences for these two vaccine groups cannot be compared.) With adjustment for period of exposure and age-group, for all SARS-Cov-2 infections, the vaccine efficacy was 30% (95% CI: -9 to 55%) for BNT162b2 and 11% (95% CI: -43 to 44%) for mRNA1273 (Table 1 & Figure 4a and 4b). For symptomatic disease, the vaccine efficacies were 43% (95% CI: 7 to 65%) and 31% (95% CI: -18 to 60%), respectively. Our study found that the fourth dose did not lead to significant adverse events despite triggering mild systemic and local symptoms in the majority of vaccine recipients. Since the fourth dose was approved in Israel for individuals over 60 years old, HCW and immunocompromised populations above 18 years, future studies will investigate the safety of the fourth dose in larger cohorts. Nevertheless, in light of numerous studies investigating the safety and reactogenicity of one, two and three mRNA vaccine doses7,11,15–17, our results suggest that the safety profile of the fourth dose is likely similar to that of previous doses. Interestingly, greater reactogenicity in younger adults compared to those aged 60 or more, which was previously reported, was mostly observed in the BNT162b2 recipients and less so in the mRNA1273 recipients. Yet, our study was not powered to identify less than 20% difference in AE rates. Our study was designed primarily to determine the immunogenicity of a fourth dose and to assess whether an mRNA heterologous fourth boost (i.e., mRNA1273 following three BNT162b2 prior doses) would be more immunogenic. Our results clearly show that both mRNA vaccines significantly induce IgG and neutralizing antibodies. Moreover, both vaccines induced ~10 folds the specific neutralizing response against Omicron and other VOC. As antibodies are found to be correlates of protection18–20 our serology results including the specific neutralizing ability against Omicron and the comparison to the third dose can also project on vaccine protection. Comparing the initial response to the fourth dose with the peak response following a third dose, did not demonstrate substantial differences in humoral response or in the amount of Omicron specific neutralizing antibodies (this study and Nemet et al.15).Overall, these data raise the possibility that the fourth dose does not boost immunity but simply restores it to peak levels. It is yet to be observed whether the waning of this fourth dose will be at a similar rate as that observed after the third dose and whether it will differ between the two mRNA vaccine groups. Overall, during the study period 25% of the control groups were infected by SARS-CoV-2 and 18-20% of the vaccinated groups had concurrent breakthrough infections, leading to a low vaccine efficacy against infections of 11-30%, with relatively wide confidence intervals. Moreover, most of the infected HCW, in all groups complained of only negligible symptoms, which in many cases would not have been tested or reported, without the active surveillance. Yet, most of these infected HCW were potentially infectious, with relatively high viral loads. Thus, the major objective for vaccinating HCW was not achieved. The increased efficacy against symptomatic compared to asymptomatic infections found in this study suggest that the fourth dose may be more efficacious against severe disease and death, as was recently observed22. Therefore, older and vulnerable populations who are at higher risk for severe disease may benefit most from a fourth vaccine dose.

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