Effectiveness of COVID-19 Viral Vector Ad.26.COV2.S Vaccine and Comparison with mRNA Vaccines in Cirrhosis.

The COVID-19 pandemic has been associated with a disruption of care and worsening outcomes of patients with liver disease. Fortunately, receipt of 2 doses of mRNA vaccine was associated with a 78.6% reduction in COVID-19 infection in cirrhosis. Although mRNA vaccines have been more widely administered in the United States, viral vector vaccines that use replication-deficient viral vectors, such as adenovirus to induce transient expression of the SARS-CoV-2 spike protein, have been the mainstay of COVID-19 vaccination worldwide. Patients with cirrhosis have vaccine hyporesponsiveness that has been observed with hepatitis B, influenza, pneumococcal, and COVID-19 mRNA vaccines. Our study aimed to determine the effectiveness of the Ad.26.COV2.S vaccine in patients with cirrhosis, and to explore how this compares with mRNA vaccines administered during the same period.

This study used participants from the Veterans Outcomes and Costs Associated with Liver disease (VOCAL) cohort assembly, which has been described in prior publications. , The date and type of COVID-19 vaccine administered from both within and outside the Veterans Affairs (VA) were identified from the VA COVID-19 shared data resource. ,

We use a test-negative case-control design, where adults (age ≥18 years) with cirrhosis who had a positive SARS-CoV-2 polymerase chain reaction (PCR) test were included as cases, and those with a negative PCR, as control subjects. Participants who were not tested for SARS-CoV-2 infection, who had prior COVID-19 before the study period, or received a liver transplant were excluded. COVID-19 cases were classified based on individual chart review using the National Institutes of Health COVID-19 severity scale. Participants were considered fully vaccinated 14 days after completion of a single dose of the Ad.26.COV2.S vaccine or after the second dose of an mRNA vaccine at the time of the SARS CoV2 PCR testing. We used propensity score matching to match test-positive cases and test-negative control subjects 1:1 on factors associated with the outcome using the Greedy matching algorithm (Supplementary Methods).

Multinomial logistic regression models were fit for COVID-19, to estimate the odds of having symptomatic illness, moderate/severe/critical illness, severe/critical illness, among participants vaccinated with either the Ad.26.COV2.S or an mRNA vaccine, compared with unvaccinated participants.

Vaccine efficacy (VE) against COVID-19 was estimated using logistic regression, comparing the odds of COVID-19 infection of fully vaccinated with unvaccinated subjects using the equation VE = 100 × (1 – adjusted odds ratio).

Of the participants in the VOCAL cohort (n = 120,952), those who did not have a COVID-19 test in the VA during the study period (n = 114,318), liver transplant recipients (n = 191), and with prior COVID-19 infection (n = 445) were excluded. That resulted in 5998 total study subjects, 968 with a positive SARS CoV2 PCR, and 5030 with a negative PCR (Supplementary Table 1). The overall cohort was predominantly male (96.3%) and white (60.5%), with a median age of 62.6 years (interquartile range, 10.5). In the propensity score (PS) matched cohort, cases and control subjects were well matched with respect to all baseline characteristics (Supplementary Table 1).

Supplementary Table 1

Descriptive Statistics for Study Patients

Variables	Full sample			Matched sample
	Case(n = 968)	Control(n = 5030)	P value	Case(n = 955)	Control(n = 955)	P value
Vaccination type, n (%)
Unvaccinated	454 (46.9)	1544 (30.7)		446 (46.7)	281 (29.4)
Pfizer BNT162b2 mRNA vaccine	274 (28.3)	1595 (31.7)	< .0001	271 (28.4)	286 (30.0)	< .0001
Moderna 1273 mRNA vaccine	199 (20.6)	1629 (32.4)		198 (20.7)	334 (35.0)
Janssen Ad.26.COV2.S vaccine	41 (4.2)	262 (5.2)		40 (4.2)	54 (5.6)
Location, n (%)
Northeast	102 (10.5)	763 (15.2)		101 (10.6)	107 (11.2)
Southeast	241 (24.9)	954 (19.0)		237 (24.8)	217 (22.7)
Midwest	190 (19.6)	1109 (22.1)	< .0001	188 (19.7)	204 (21.4)	.7352
South	246 (25.4)	1120 (22.3)		241 (25.2)	225 (23.6)
Northwest	54 (5.6)	392 (7.8)		54 (5.7)	57 (6.0)
Southwest	135 (13.9)	692 (13.8)		134 (14.0)	145 (15.2)
Sex, n (%)
Male	925 (95.6)	4849 (96.4)	.2048	923 (96.7)	923 (96.7)	1.0000
Female	43 (4.4)	181 (3.6)		32 (3.3)	32 (3.3)
Age, y, median (IQR)	62.1 (10.5)	62.7 (10.5)	.0831	62.2 (10.6)	62.4 (11.2)	.5306
White, n (%)	598 (61.8)	3030 (60.2)	.8353	595 (62.3)	595 (62.3)	1.0000
BMI, median (IQR)	30.0 (8.1)	29.0 (7.8)	< .0001	30.0 (8.0)	30.0 (8.5)	.9635
Diabetes, n (%)	579 (59.8)	2481 (49.3)	< .0001	574 (60.1)	550 (57.6)	.2645
Current smoker, n (%)	586 (60.5)	3296 (65.5)	.0029	577 (60.4)	563 (59.0)	.5137
Alcohol, n (%)	254 (26.2)	1331 (26.5)	.8862	250 (26.2)	239 (25.0)	.5641
AUDIT-C score, n (%)
Low	768 (79.3)	3809 (75.7)	.0155	759 (79.5)	754 (79.0)	.7780
High	200 (20.7)	1221 (24.3)		196 (20.5)	201 (21.0)
Cirrhosis comorbidity, n (%)
0	97 (10.0)	483 (9.6)	.0568	97 (10.2)	107 (11.2)	.8551
1 + 0	214 (22.1)	1346 (26.8)		205 (21.5)	200 (20.9)
1 + 1	259 (26.8)	1311 (26.1)		257 (26.9)	268 (28.1)
3 + 0	39 (4.0)	208 (4.1)		39 (4.1)	34 (3.6)
3 + 1	352 (36.4)	1660 (33.0)		350 (36.7)	342 (35.8)
5 + 0	1 (0.1)	1 (0.02)		1 (0.1)	0 (0.0)
5 + 1	6 (0.6)	21 (0.4)		6 (0.6)	4 (0.4)
eCTP class, n (%)
A	763 (78.8)	4058 (80.7)	.3952	752 (78.7)	769 (80.5)	1.0000
B	182 (18.8)	856 (17.0)		180 (18.9)	167 (17.5)
C	23 (2.4)	116 (2.3)		23 (2.4)	19 (2.0)
Baseline laboratory results, median (IQR)
Alanine aminotransferase, IU/mL	40.0 (45.2)	42.0 (49.0)	.1304	40.0 (45.5)	43.0 (47.0)	.0905
Platelet count, × 10E9/L	147.0 (91.0)	151.0 (90.0)	.1471	147.0 (91.2)	151.0 (88.8)	.3632
Creatinine, mg/dL	0.9 (0.4)	0.9 (0.3)	.1667	0.9 (0.3)	0.9 (0.3)	.5657
Total bilirubin, mg/dL	0.9 (0.7)	0.8 (0.7)	.3491	0.9 (0.7)	0.8 (0.7)	.4925
International normalized ratio	1.1 (0.2)	1.1 (0.2)	.1373	1.1 (0.2)	1.1 (0.2)	.4592
MELD-Na	8.0 (6.0)	8.0 (5.0)	.3463	8.0 (6.0)	8.0 (6.0)	.5567

NOTE: Bold values indicate P value < .05.

AUDIT-C, Alcohol Use Disorders Identification Test-Concise; BMI, body mass index; eCTP, electronic Child-Pugh-Turcotte; IQR, interquartile range; MELD-Na, Model for End-Stage Liver Disease adding Serum Na Parameter.

The PS matched cohort had 1910 participants, of whom 94 (4.9%) received the Ad.26.COV2.S vaccine, 1089 (57.0%) an mRNA vaccine, and 727 (38.0%) were unvaccinated. Severe or critical COVID-19 was seen in 73 (6.7%) of participants who received the mRNA vaccine, 7 (7.4%) of those who received the viral vector vaccine, and 89 (12.2%) of those who were unvaccinated, in the PS matched cohort.

VE of the Ad.26.COV2.S vaccine against COVID-19 was 64% (odds ratio [OR], 0.36; 95% confidence interval [CI], 0.20–0.62; P = .005) (Supplementary Table 2 and Figure 1 ). Effectiveness was 68% against symptomatic illness (OR, 0.32; 95% CI, 0.21–0.41; P = .03), 70% against moderate/severe/critical COVID-19 (OR, 0.30; 95% CI, 0.26–0.37; P = .046), and 72% against severe/critical COVID-19 (OR, 0.28; 95% CI, 0.16–0.42; P = .006).

Supplementary Table 2

VE and Noninferiority Assessment for the Risk of Different COVID-19 Criteria in Patients Who Received Ad.26.COV2.S, BNT162b2/mRNA-1273 Vaccines Versus Unvaccinated Control Subjects

VE = 1-OR		Symptomatic COVID-19	Moderate/severe/critical COVID-19	Severe/critical COVID-19
	COVID-19
Ad.26.COV2.S
Upper confidence limit	0.64	0.68	0.7	0.72
VE	0.8	0.79	0.74	0.84
LCL	0.38	0.59	0.63	0.58
BNT162b2 / mRNA-1273
Upper confidence limit	0.73	0.78	0.8	0.82
VE	0.81	0.84	0.92	0.93
LCL	0.63	0.62	0.68	0.69
90% NIM	0.567	0.558	0.612	0.621
Conclude noninferiorityLCL (Ad.26.COV2.S) <90% NIM	No	Yes	Yes	No
75% NIM	0.4725	0.465	0.51	0.5175
Conclude noninferiorityLCL (Ad.26.COV2.S) <75% NIM	No	Yes	Yes	Yes

LCL, lower confidence limit; NIM, noninferiority margin; VE, vaccine efficacy.

Figure 1

Odds ratio (95% confidence interval) of (A) COVID-19, (B) symptomatic COVID-19, (C) moderate/severe/critical COVID-19, and (D). severe/critical COVID-19 among participants with cirrhosis who received the Janssen Ad.26.COV2.S vaccine, or the Moderna 1273-mRNA/Pfizer BNT162b2 mRNA vaccines.

VE of the mRNA vaccines against COVID-19 was 73% (OR, 0.27; 95% CI, 0.19–0.37; P < .0001). Effectiveness was 78% against symptomatic illness (OR, 0.22; 95% CI, 0.16–0.38; P = .03), 80% against moderate/severe/critical COVID-19 (OR, 0.20; 95% CI, 0.08–0.32; P = .003), and 82% against severe/critical COVID-19 (OR, 0.18; 95% CI, 0.07–0.31; P = .002) (Supplementary Table 2 and Figure 1).

We also performed a noninferiority analysis for each of the outcomes, to compare the 2 vaccines directly. We identified the noninferiority margin as 90% of the lower limit of the 95% CI of the BNT162b2/mRNA-1273 VE. Using the 90% noninferiority margin, we conclude that Ad.26.COV2.S is noninferior to the mRNA vaccines for outcomes of symptomatic and moderate/severe/critical COVID-19. However, if we use a more liberal noninferiority margin (75%), we conclude noninferiority against outcomes of symptomatic, moderate/severe/critical, and severe/critical COVID-19 (Supplementary Table 2).

In this study of participants with cirrhosis, we observe that vaccination with a single dose Ad.26.COV2.S vaccine is modestly effective (64%) against overall COVID-19 and performs better against severe/critical COVID-19 (72%). These numbers are comparable with the effectiveness of mRNA vaccines against both COVID-19 (73%) and severe/critical COVID-19 (82%). We also observe no statistically significant differences between the viral vector and mRNA vaccines. The findings are consistent with data reporting high immunogenicity of the COVID-19 vaccines in patients with cirrhosis. ,

Strengths of this study include its test-negative case-control study design, which has been used to estimate vaccine effectiveness against medically attended, laboratory-confirmed SARS-CoV-2 infection among patients who receive testing for SARS-CoV-2 infection.

Limitations include possible residual confounding and the limited number of females. Despite propensity matching, the low number of participants who received the Ad.26.COV2.S vaccine is a limitation, and the viral vector vaccine group is underpowered. These findings take into account the influence of the Delta, but not the Omicron variant. There is the possibility that participants could have received the vaccine or tested positive for COVID-19 outside the VA, but this is unlikely to differ between cases and control subjects. Finally, these data were collected before the administration of booster doses of the BNT162b2 vaccine for immunocompromised patients and the more recent recommendation for boosters for all adults in the United States.

In conclusion, a single dose of the Ad.26.COV2.S vaccine has a 64% vaccine effectiveness against COVID-19, with a 72% effectiveness against severe/critical COVID-19.