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The new england journal of medicine
n engl j med 385;22 nejm.org November 25, 2021Correspondence
Effectiveness of BNT162b2 Vaccine against
Delta Variant in Adolescents
To the Editor: The B.1.617.2 (delta) variant of
seve
re acute respiratory syndrome coronavirus 2
(SARS-CoV-2) has emerged as the dominant strain
circulating in many regions worldwide. The BNT162b2 mRNA vaccine against coronavirus disease 2019 (Covid-19) was found to be effective in preventing infection with the delta variant in a recent observational study,
1 but other reports
have suggested reduced vaccine effectiveness against this variant.
2,3 On May 10, 2021, the U.S.
Food and Drug Administration approved the emergency use of BNT162b2 in adolescents 12 years of age or older on the basis of a clinical trial that had been conducted before the delta variant had become prevalent in the United States.
4 Additional evidence was needed regard-
ing the effectiveness of the BNT162b2 vaccine among adolescents, particularly against the delta variant.
We sought to estimate the vaccine effective-
ness of BNT162b2 against the delta variant among vaccinated adolescents for whom an un-vaccinated match was found. We used data from Clalit Health Services, the largest health care organization in Israel, to conduct an observa-tional cohort study involving adolescents be-tween the ages of 12 and 18 years who had no prior SARS-CoV-2 infection noted in their elec-tronic medical record and who had been vacci-nated between June 8 and September 14, 2021. According to the sequencing of samples ob-tained from infected persons that was performed by the Israeli Ministry of Health during this pe-riod, the delta variant was responsible for more than 95% of new infections in the general popu-lation in Israel.
We used the same methods that were used in
our previous studies of vaccine effectiveness, which were conducted in the same health care organization using the same database.
5 (See the
Methods section in the Supplementary Appen-dix, available with the full text of this letter at NEJM.org.) Vaccine effectiveness was defined as 1 minus the risk ratio, which was estimated over several follow-up periods for documented SARS-CoV-2 infection and symptomatic Covid-19. More severe outcomes related to Covid-19 are rare in this age group.
Of 184,905 vaccinated adolescents, 130,464
met the eligibility requirements, and 94,354 of these vaccine recipients were successfully matched with 94,3 54 unvaccinated controls (Fig. S1 and the Methods section in the Supplementary Ap-pendix). The eligible population was similar to the matched population with respect to several demographic and clinical characteristics (Tables
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The new england journal of medicine
n engl j med 385;22 nejm.org November 25, 2021S1 and S2). The frequency of polymerase-chain-
reaction testing for SARS-CoV-2 was similar in the vaccinated and unvaccinated populations (9.4 and 9.9 tests per 100 persons per week, re-spectively). The median follow-up was 27 days after baseline, which was defined as the admin-istration of the first dose among the vaccine re-cipients. Kaplan–Meier curves for SARS-CoV-2 infection in both the vaccinated and unvacci-nated groups were similar during the initial days, after which the incidence began to rise more slowly in the vaccinated group (Table 1 and Fig. S2).
The estimated vaccine effectiveness against
documented SARS-CoV-2 infection was 59% (95% confidence interval [CI], 52 to 65) on days 14 through 20 after the first dose, 66% (95% CI, 59 to 72) on days 21 to 27 after the first dose, and 90% (95% CI, 88 to 92) on days 7 to 21 after the second dose. The estimated vaccine effec-tiveness against symptomatic Covid-19 was 57% (95% CI, 39 to 71) on days 14 to 20 after the first dose, 82% (95% CI, 73 to 91) on days 21 to 27 after the first dose, and 93% (95% CI, 88 to 97) on days 7 to 21 after the second dose.
In a recent randomized trial involving 1983
vaccinated adolescents between the ages of 12 and 15 years with no history of SARS-CoV-2 in-fection, investigators estimated that the vaccine effectiveness of two doses of BNT162b2 was 100% (95% CI, 75 to 100) against symptomatic infection by non-delta variants.
4 The present
observational study provides substantially more precise estimates of vaccine effectiveness among adolescents between the ages of 12 and 18 years for both documented infection and symptomatic disease in a setting in which the delta variant was predominant. Our estimates of the effec-tiveness of two doses of the BNT162b2 vaccine against the delta variant among adolescents are similar to estimates of effectiveness against the alpha variant in the general population with the use of the same study design
5 and are similar to
the estimate of 88% (95% CI, 85 to 90) against the delta variant in the general population in an observational study that used a different design.
1
Our results show that the BNT162b2 mRNA
vaccine was highly effective in the first few weeks after vaccination against both document-ed infection and symptomatic Covid-19 with the delta variant among adolescents between the ages of 12 and 18 years.Table 1. Effectiveness of BNT162b2 Vaccine among Adolescents.*
Time Period Documented SARS-CoV-2 Infection Symptomatic Covid-19
Unvaccinated
GroupVaccinated
GroupVaccine
Effectiveness
(95% CI)Risk Difference
(95% CI)Unvaccinated
GroupVaccinated
GroupVaccine
Effectiveness
(95% CI)Risk Difference
(95% CI)
events (no. at risk) %no. of events/
100,000 persons events (no. at risk) %no. of events/
100,000 persons
Days 14–20 after
first dose463
(69,408)192
(69,609)59
(52–65)436.5
(363.1–510.2)95
(70,203)41
(70,227)57
(39–71)86.1
(49.0–123.7)
Days 21–27 after
first dose400
(56,997)137
(57,358)66
(59–72)514.7
(423.1–590.6)84
(57,803)15
(57,878)82
(73–91)133.0
(101.1–169.4)
Days 7–21 after
second dose818
(46,384)79
(46,815)90
(88–92)2032.7
(1866.3–2184.6)151
(47,194)11
(47,303)93
(88–97)379.6
(317.0–451.3)
* Data are for adolescents between the ages of 12 and 18 years who were members of Clalit Health Services from June 8 to September 14, 2021. The study population included 94,354
adolescents in both the unvaccinated and vaccinated groups.
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Correspondence
n engl j med 385;22 nejm.org November 25, 2021Ben Y. Reis, Ph.D.
Boston Children’s Hospital
Boston, MA
Noam Barda, M.D.
Michael Leshchinsky, M.S. Eldad Kepten, Ph.D.
Clalit Research Institute Tel Aviv, Israel
Miguel A. Hernán, M.D. Marc Lipsitch, D.Phil.
Harvard T.H. Chan School of Public Health Boston, MA
Noa Dagan, M.D.
Ran D. Balicer, M.D.
Clalit Research Institute Tel Aviv, Israel [email protected]
Drs. Reis and Barda and Drs. Dagan and Balicer contributed
equally to this letter.
Supported by the Ivan and Francesca Berkowitz Family Living
Laboratory Collaboration at Harvard Medical School and Clalit Research Institute.Disclosure forms provided by the authors are available with
the full text of this letter at NEJM.org.
This letter was published on October 20, 2021, at NEJM.org.
1.Lopez Bernal J, Andrews N, Gower C, et al. Effectiveness of
Covid-19 vaccines against the B.1.617.2 (Delta) variant. N Engl J
Med 2021; 385: 585-94.
2.Puranik A, Lenehan PJ, Silvert E, et al. Comparison of two
highly-effective mRNA vaccines for COVID-19 during periods ofAlpha and Delta variant prevalence. August 21, 2021 (https://www . medrxiv . org/ content/ 10 . 1101/ 2021 . 08 . 06 . 21261707v3). pre-
print.
3.Herlihy R, Bamberg W, Burakoff A, et al. Rapid increase in
circulation of the SARS-CoV-2 B.1.617.2 (Delta) variant — Mesa
County, Colorado, April–June 2021. MMWR Morb Mortal WklyRep 2021; 70: 1084-7.
4. Frenck RW Jr, Klein NP, Kitchin N, et al. Safety, immunoge-
nicity, and efficacy of the BNT162b2 Covid-19 vaccine in adoles-cents. N Engl J Med 2021; 385: 239-50.
5.Dagan N, Barda N, Kepten E, et al. BNT162b2 mRNA Cov-
id-19 vaccine in a nationwide mass vaccination setting. N Engl JMed 2021; 384: 1412-23.
DOI: 10.1056/NEJMc2114290
Vaccine-Induced Thrombocytopenia with Severe Headache
To the Editor: Vaccine-induced immune throm-bot
ic thrombocytopenia (VITT), a serious adverse
event after vaccination with ChAdOx1 nCoV-19 (AstraZeneca) or Ad26.COV2.S (Johnson & John-son–Janssen), is caused by platelet factor 4 (PF4)–dependent, platelet-activating antibodies.
1-3 High-
dose immune globulins and anticoagulation are the main treatments.
4,5 In this report, we present
evidence that vaccine-induced thrombocytopenia (VIT) without associated cerebral venous sinus thrombosis (CVST) or other thromboses and with severe headache as the heraldic symptom may precede VITT (“pre-VITT syndrome”).
Eleven patients presented with severe head-
ache in the absence of CVST 5 to 18 days after ChAdOx1 nCoV-19 vaccination. All the patients had thrombocytopenia, high
D-dimer levels, and
high levels of anti–PF4–heparin IgG antibodies. During follow-up, intracranial hemorrhage oc-curred in three patients (Patients 1, 2, and 3), with radiologic evidence of new CVST in Patients 2 and 3 (Fig. 1, and Table S1 in the Supplemen-tary Appendix, available with the full text of this letter at NEJM.org). Only two patients (Patients 2 and 4) were initially admitted with conditions that met the criteria for VITT; both patients had pulmonary embolism, and additional splanchnic vein thrombosis was present in Patient 2. In Patient 2, anticoagulation treatment had been initiated several days earlier for pulmonary em-bolism (without diagnosis of VITT) but was stopped after the onset of headache, shortly be-fore CVST developed. In two patients (Patients 1 and 3), peripheral thromboses were eventually identified during follow-up. Thrombotic compli-cations did not develop in seven of the patients (Patients 5 through 11); all but one of these pa-tients received high-dose immune globulin, gluco-corticoids, or therapeutic-dose anticoagulation within 5 days after headache onset. In contrast, in all four patients with subsequent thrombosis (Patients 1 through 4), therapeutic-dose antico-agulation either was not started until 6 to 9 days after headache onset or was stopped prema-turely before the development of CVST.
Although the combination of thrombocytope-
nia and severe headache due to CVST has been recognized as the typical presentation of VITT,
1,2
the experience with these 11 patients suggests that VIT with severe headache, elevated
D-dimer
levels, and strongly positive results on anti–PF4–heparin IgG enzyme-linked immunosorbent as-say may precede VITT.
Our findings have immediate implications
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