Rate and risk factors for breakthrough SARS-CoV-2 infection after vaccination.

To the Editor,

We read with interest the recent article by Sansone et al. regarding the effectiveness of BNT162b2 vaccine against the B.1.1.7 variant of SARS-CoV-2 among healthcare workers in Brescia, Italy. Recently available data from other groups also confirms very high levels of effectiveness of the Pfizer-BNT-162b2 vaccine in the real-world settings.2, 3, 4, 5, 6 Despite such high efficacy and effectiveness, there are anecdotal reports of breakthrough infection among vaccine recipients. Clinical characteristics and risk factors for SARS-CoV-2 infection after a full recommended course of vaccination is not known. We report the rate and risk factors associated with infection among US Veterans who received a recommended course of vaccination. The Veterans Health Administration (VA) is the largest provider of integrated health services in the United States. The VA provides care to over 9 million enrolled Veterans at 170 VA medical centers and 1074 outpatient sites.

Methods

Creation of the study dataset

We identified all Veterans who received two doses of the Pfizer-BNT-162b2 or Moderna-mRNA-1273 vaccine between December 15, 2020 and March 31, 2021 from the national VA COVID-19 Shared Data Resource. We excluded those with a positive SARS-CoV-2 PCR on a nasopharyngeal swab within 14 days of receiving the first vaccine dose. From the remaining persons, we retained those who had at least one SARS-CoV-2 PCR test performed on a nasopharyngeal swab ≥7 days after the second dose vaccine dose. Cases were those with confirmed SARS-CoV-2 infection and controls were those who remained uninfected with at least one confirmed negative test for SARS-CoV-2 ≥ 7 days after their second vaccine dose.

Results

Among a total of 258,716 fully vaccinated persons, we identified 410 persons with breakthrough infection and 14,465 controls. Median age (IQR) was 73 (68,78) years for the infected group and 72 (66,76) for the uninfected group (P = 0.0002). There were more Whites in the infected group (76.6% vs. 69.1%; P = 0.01)) compared with the uninfected group. Prevalence of comorbidities was similar in the two groups except anemia, which was more common in the infected group.

Overall infection rate ≥7 days after the second vaccine dose was 0.66 (95% CI 0.60,0.72) per 1000 person-days of follow up. (Table 1 ) The rates were not statistically significantly different by age group, sex, or the type of vaccine administered. Rate was lower among Black compared with Whites (0.49 [95% CI 0.37,0.60] vs 0.73 [95% CI 0.65,0.81] per 1000 person-years; P = 0.002) and among those with no comorbidities (0.44 [95% CI 0.25,0.62]) compared with those with 1–3 comorbidities (0.68 [95% CI 0.59,0.76]; P = 0.05) and those with 4 or more comorbidities (0.69 [95% CI 0.57,0.81]; P = 0.05).

Table 1

Infection rate per 1000 person-days ≥7 days after second vaccine dose, by subgroups.

	N	Rate (95% CI)	P-Value
Infection rate, overall	410	0.66 (0.60,0.72)	N/A
By age
<=40	6	0.41 (0.08,0.73)	comparator
>40 – 60	41	0.54 (0.37,0.70)	0.53
>60 – 70	96	0.60 (0.48,0.72)	0.36
>70	267	0.72 (0.637,0.81)	0.16
By race
White	314	0.73 (0.65,0.81)	comparator
Black	70	0.49 (0.37,0.60)	0.002
Other/Unknown	26	0.54 (0.33,0.74)	0.13
By sex
Female	24	0.69 (0.42,0.97)	comparator
Male	386	0.66 (0.59,0.72)	0.81
By comorbidities
None	22	0.44 (0.25,0.62)	comparator
1–3	257	0.68 (0.59,0.76)	0.05
4 or more	131	0.69 (0.57,0.80)	0.05
By vaccine type
Pfizer	266	0.69 (0.60,0.77)	comparator
Moderna	144	0.62 (0.52,0.72)	0.32

In a Cox proportional hazards model, factors associated with SARS-CoV-2 infection included increasing age (HR 1.11; 95% CI 1.01,1.23), Black race (HR 0.65; 95% CI 0.50,0.85), and presence of anemia (HR 1.37; 95% CI 1.09,1.73). (Table 2 ) Increasing number of comorbidities was not associated with a higher risk of infection while other factors demonstrated similar hazards ratios.

Table 2

Factors associated with SARS-CoV-2 infection after vaccination (infection ≥7 days after second vaccine dose; Cox proportional hazards model).

	Hazards ratio (95% CI)	P-value
Age (per 10 years increase)	1.11 (1.01,1.23)	0.04
Race (comparator: White)
Black	0.65 (0.5,0.85)	0.001
Other/unknown	0.75 (0.5,1.13)	0.17
Body mass index >30 (comparator: <30)	0.91 (0.73,1.12)	0.36
Comorbidities
Diabetes	1.1 (0.9,1.35)	0.36
Coronary artery disease	0.97 (0.79,1.2)	0.78
Chronic kidney disease	1.11 (0.88,1.39)	0.38
Chronic lung disease (COPD)	0.88 (0.72,1.08)	0.21
Anemia (Hb<13 for men; <12 for women)	1.37 (1.09,1.73)	0.01
Cancer diagnosis	0.86 (0.7,1.05)	0.14
Human immunodeficiency virus infection	0.38 (0.1,1.54)	0.18
Vaccine type (comparator: Pfizer)
Moderna	0.82 (0.67,1.01)	0.06

Discussion

To our knowledge, this is the first study to describe the rate and risk factors for SARS-CoV-2 breakthrough infection in persons who have been fully vaccinated. We found a low rate of infection among those who were fully vaccinated and age, race and anemia to be associated with confirmed infection.

We found relatively few factors associated with infection after vaccination. Increasing age increased the risk, as did presence of anemia at baseline. Increasing age is a well-recognized risk factor for SARS-CoV-2 infection and is also associated with more severe disease and poorer clinical outcomes. Therefore, it is not surprising that it would also be associated with infection after vaccination. Multiple comorbid conditions are also associated with a higher risk and increased severity of infection. The reason for the association of anemia with infection after vaccination while no association was demonstrable other comorbidities is unclear. While we used the standard World Health Organization definition of anemia (i.e. hemoglobin <13 g/dL for men and <12 g/dL for women), this may be too permissive. We did not assess the association of the degree of anemia with the risk of infection. Whether this association is limited to more severe anemia, which may worsen oxygenation, is not known.

Surprisingly, Black race was associated with a lower risk of infection. The reason for this is entirely unclear. It is possible that the Blacks who were vaccinated were younger and healthier and at a lower risk of infection at the outset. It is equally possible that they were older and less healthy and due to those reasons they were less mobile and therefore less likely to be exposed to persons with confirmed infection. Further studies are warranted to confirm this finding and to understand the reasons for this finding.

Our study has several strengths. We studied a national population with diverse geographical and demographic characteristics who receive care within a single integrated healthcare network. Vaccines, SARS-CoV-2 testing, and clinical care are provided free or cost or with minimal expense to qualified Veterans. The VA created a national database of SARS-CoV-2 infected Veterans using validated definitions and algorithms which is regularly updated and provides a rich resource for clinical and observational studies. Despite these strengths, several limitations need to be noted. Veterans are predominantly male. We did not assess the actual exposure to confirmed cases. We also did not assess the clinical severity of disease and outcomes in our study population, which will be the subject of a subsequent study.

In conclusion, the rate of infection among persons who have been fully vaccinated is low but not insignificant. Increasing age and presence of anemia increase the risk, while Black race is associated with a lower risk. An awareness campaign, particularly targeted to those at risk is needed to mitigate the risk.

Authorship statement

Dr. Butt had complete access to data at all times and accepts the responsibility of the integrity of this article.

Disclosures

Dr. Butt has received grants (to the institution) from Gilead Sciences. Other authors have no relevant disclosures. Dr. Mayr is supported by K23GM132688 from the National Institutes of Health.

Funding

None