Correspondence

Vaccine Breakthrough Infections with SARS-CoV-2 Variants

To the Editor

The article by Hacisuleyman et al. (published online on April 21)1 reinforces concerns about SARS-CoV-2 variants and vaccine breakthrough. The authors describe two fully vaccinated women older than 50 years of age in whom subsequent vaccine breakthrough infection occurred with variants.

The authors did not report on the measurement of SARS-CoV-2Cspecific T-cell responses. T-cell immunity is important in the control of SARS-CoV-22 and may be critical for potential cross-reactive protection against variants. SARS-CoV-2 messenger RNA (mRNA) vaccines generate weaker T-cell responses than other vaccine platforms.3 Although several mix-and-match vaccine studies are ongoing or planned, the effect of a vector boost of an mRNA vaccine prime on T-cell responses is currently unknown.

Since Covid-19 vaccines vary with regard to immunogenicity and immune specificity, we would encourage consideration of a vaccine boost from a T-cellCskewed vaccine after mRNA vaccination to boost T-cell responses and potentially to reduce the chance of breakthrough infection through the generation of cross-protective T-cell immunity. The prevention of vaccine failure due to variants is a critical part of pandemic management.

Douglas F. Nixon, M.D., Ph.D.
Lishomwa C. Ndhlovu, M.D., Ph.D.
Weill Cornell Medicine, New York, NY

No potential conflict of interest relevant to this letter was reported.

This letter was published on June 2, 2021, at NEJM.org.

  1. 1. Hacisuleyman E, Hale C, Saito Y, et al. Vaccine breakthrough infections with SARS-CoV-2 variants. N Engl J Med 2021;384:2212-2218.

  2. 2. Sette A, Crotty S. Adaptive immunity to SARS-CoV-2 and COVID-19. Cell 2021;184:861-880.

  3. 3. Klasse PJ, Nixon DF, Moore JP. Immunogenicity of clinically relevant SARS-CoV-2 vaccines in nonhuman primates and humans. Sci Adv 2021;7(12):eabe8065-eabe8065.

To the Editor

Hacisuleyman et al. report an incidence of breakthrough infection of 0.5% in a cohort of 417 health care workers who received both doses of BNT162b2 (PfizerCBioNTech) or mRNA-1273 (Moderna) vaccine. Here, we present data regarding breakthrough infections in a cohort of health care workers in a tertiary care hospital in India who received ChAdOx1 nCoV-19 (recombinant) vaccine. Among 12,248 health care workers, 7170 (58.5%) received the first dose of vaccine, with 3650 (29.8%) subsequently receiving the second dose, in accordance with guidelines from the government of India.1 A total of 5078 health care workers (41.5%) were unvaccinated.

Vaccination Status or Timing of Positive Test Result among 506 Health Care Workers Who Tested Positive for SARS-CoV-2, January 16 to April 17, 2021.

Health care workers who tested positive for SARS-CoV-2 after receipt of the first dose of vaccine were those who tested positive at any time between receipt of the first and second doses. Health care workers who tested positive after receipt of the second dose were those who tested positive at any time from receipt of the second dose to 14 days later. Breakthrough infection was defined as a positive test after the health care worker was considered to be fully vaccinated (i.e., >14 days after receipt of the second dose). Percentages may not total 100 because of rounding.

Since the start of the vaccination program, 506 health care workers have tested positive for SARS-CoV-2. The vaccination status of the health care workers who tested positive is shown in Figure 1. A total of 184 of 7170 health care workers (2.6%) tested positive after receiving at least one dose of vaccine; the median time between receipt of the first dose and the positive test was 44 days (interquartile range, 25 to 59). A total of 72 of 3650 health care workers (2.0%) tested positive after the second dose; the median time from receipt of the second dose to the positive test was 20 days (interquartile range, 11 to 34). Among the health care workers who received both doses and completed at least 14 days of follow-up after the second dose, the incidence of breakthrough infection was 1.6% (48 of 3000 health care workers); the median time from receipt of the second dose to breakthrough infection was 29.5 days (interquartile range, 20 to 35).

Kirtan Rana, M.D.
Ritin Mohindra, M.D.
Lakshmi Pinnaka, M.D.
Postgraduate Institute of Medical Education and Research, Chandigarh, India

No potential conflict of interest relevant to this letter was reported.

This letter was published on June 2, 2021, at NEJM.org.

  1. 1. Indias Covid-19 vaccine campaign off to a roaring start. The Hindu Business Line. January 16, 2021 (https://www.thehindubusinessline.com/news/national/indias-vaccines-enjoy-global-credibility-because-of-their-track-record-pm-modi/article33585938.ece).

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Response

The authors reply: Nixon and Ndhlovu note the importance of considering T-cell responses to Covid-19. This suggestion seems prudent, and as they note, current vaccines may produce various T-cell responses. We also agree that the data published to date do not discriminate well among various kinds of T-cell responses (types 1, 2, and 17 helper and regulatory T cells [i.e., Th1, Th2, Th17, and Treg]). These may be of importance in careful monitoring after infection and after vaccination,1 particularly given concerns about autoimmunity in the context of Covid-19.

Rana et al. followed a large cohort of health care workers with breakthrough infection after full vaccination. We believe that this and related efforts to gather additional data provide important contributions regarding risk. It is worth noting that breakthrough infection itself does not distinguish between vaccine failure and breakthrough after successful vaccination. In our article, we underscore the importance of an admittedly challenging strategy for doing so: serial testing of asymptomatic persons, which has the potential to identify neutralizing antibodies in acute (as compared with convalescent) serum, along with assays testing the quality and duration of T-cell and B-cell responses. It will be especially important to combine data acquisition with clinical information regarding the course of persons with breakthrough infection and to track their immune responses along with the viral sequence in order to correlate these variables with variants.

Nathalie E. Blachere, Ph.D.
Ezgi Hacisuleyman, Ph.D.
Robert B. Darnell, M.D., Ph.D.
Rockefeller University, New York, NY

Since publication of their article, the authors report no further potential conflict of interest.

This letter was published on June 2, 2021, at NEJM.org.

  1. 1. Graham BS. Rapid COVID-19 vaccine development. Science 2020;368:945-946.

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