Does COVID-19 Vaccination with BNT162b2 Influence HIV-Related Immunological and Virological Markers? Data from 235 Persons Living with HIV at Cotugno Hospital,Naples,Italy: Immune Response After Second and Third Doses,and Influence on Immunovirological Markers

Abstract

Few data are available on the impact of COVID-19 vaccination on CD4 counts and HIV-RNA in persons living with HIV (PLWH). We present the data of 235 PLWH who were vaccinated with BNT162b2 in March 2021–February 2022 at the “Cotugno” hospital in Naples. PLWH treated at the “Cotugno” hospital, who were vaccinated at the hospital vaccination center, without prior COVID-19 and for whom immunological/virological data were available in the last 12 months and in the 6 months after vaccination were included. Antispike Ab were available for 187 and 64 PLWH after the second and third doses: PLWH with antispikes >33 binding antibodies units (BAU)/mL increased from 91% to 98%. Antinucleocapsid Ab performed in 147 and 56 patients identified 19 (13%) asymptomatic/paucisymptomatic COVID-19 infections after the second dose and an additional 15 (27%) after the third dose. Immunological/virological data were collected before vaccination (T0), after the second dose (T1), and after the third dose (T2). The absolute number of CD4 increased after the third dose (median 663, 657, and 707 at T0, T1, and T2; p < 0.000 T0 vs. T2). The proportion of patients with HIV-RNA <50 copies/mL increases significantly after the second dose (73%; 85.7%; 87.7%; p < 0.000 T0 vs. T2). The presence of COVID-19 asymptomatic/paucisymptomatic infections (demonstrated by the presence of antinucleocapsid Ab) significantly increases SARS-CoV-2 antispike Ab after second dose, but not after third dose. Asymptomatic/paucisymptomatic COVID-19 infections do not have influence on CD4 cell number and HIV-RNA level. Similarly, the presence of not-controlled HIV-RNA (HIV-RNA >50 copies/mL) does not influence antispike Ab response. According to our data, the response to SARS-CoV2 vaccination is effective in people living with HIV. Vaccination against COVID-19 appears to positively affect immunological and virological levels in people living with HIV.

Introduction

Although with differences between different studies, people with chronic HIV infection (persons living with HIV [PLWH]) showed higher hospitalization and mortality rates for COVID-19 (Bhaskaran et al., 2021; Geretti et al., 2021; Tesoriero et al., 2021), such being identified as at-risk population for severe COVID-19. Consequently, vaccination campaigns have involved PLWH since their beginning.

Almost all studies are concordant to report a good humoral and T cell immune response in PLWH on anti-retroviral therapy (ART) and with CD4 count >200 cells/μL after administration of primary cycle and booster dose of mRNA vaccines for COVID-19. Immune response in this population is comparable with that of HIV-free population. Most of studies, moreover, suggest a lower immune response among PLWH with CD4 count <200 cells/μL (Antinori et al., 2022; Brumme et al., 2021; González de Aledo et al., 2022; Jedicke et al., 2022; Levy et al., 2021; Lombardi et al., 2022; Ruddy et al., 2021; Vergori et al., 2022; Woldemeskel et al., 2022).

On the contrary, poor data are available on the impact of COVID-19 vaccination on main viroimmunological markers in PLWH: HIV-RNA and CD4 count (Portillo et al., 2022). In the past, administration of AS03-adjuvanted influenza vaccine in PLWH resulted not only in a strong serological response but also in a transient effect of increased HIV-1 RNA level in participants with a previously well-controlled infection (Calmy et al., 2012). Similarly, impact of vaccine immune stimulation on CD4 dynamics is unknown.

The main objectives of this study are to describe (1) immunological response against COVID-19 to primary cycle and booster dose of BNT162b2, and (2) impact of vaccination on HIV-RNA levels and CD4 counts among 235 PLWH followed up at “D. Cotugno” hospital, Naples, Southern Italy. We also explored the impact of asymptomatic/paucisymptomatic COVID-19 infections, determined by positive antinucleocapsid Ab, on antispike levels, CD4 count, and HIV-RNA level.

Materials and Methods

Study design

This is a retrospective observational study exploring immunological response to COVID-19 BNT162b2 vaccine, and its influence on virological and immunological markers (HIV-RNA and CD4 count) in a population of PLWH in care at “D. Cotugno” hospital, Naples, Southern Italy.

Setting

The study setting is the “D. Cotugno” hospital, a monospecialistic infectious disease referral center sited in Naples, Campania, Southern Italy. Campania is the most populous region in Southern Italy, accounting for 6 million inhabitants. The “D. Cotugno” hospital has a long-term tradition in HIV/AIDS care, and some medical units are mainly dedicated to in-patient and outpatient management of PLWH. Specific HIV diagnostics are performed within the hospital laboratory. A vaccination facility was established within the hospital during the COVID-19 pandemic. A total of ∼2,500 PLWH are in care at “D. Cotugno” hospital, accounting for ∼70% of PLWH in Campania Region.

Participants and data source

A sample of patients with HIV/AIDS in care at “D. Cotugno” hospital, those referring to two HIV/AIDS Units and accounting for 50% of the entire PLWH hospital population, represented the source population of the study. Among them, we define the following as inclusion criteria: (1) those patients who get vaccinated at Cotugno Vaccination facility, (2) for patients whom immunological and virological data were available in the 12 months before and in the 6 months after vaccination, and (3) for those whom no previous COVID-19 infection was known or detected by the presence of antinucleocapsid Ab during the study period.

Based on these criteria, 235 patients were included. All patients received two or three doses of BNT162b2 (Comirnaty Pfizer/BioNTech) in the period from January 2021 to June 2022. Data source for vaccination included the electronic records at Vaccination facility. Demographical, clinical, immunological, and virological data were regularly collected during the periodical follow-up visits. For study purposes, these data were obtained from clinical electronic database for patients' records.

Variables

The main outcomes of the study are represented as follows: (1) the level of antispike Ab for COVID-19 after the second and the third dose of BNT162b2. The determination of antispike Ab was carried out with chemiluminescence (SARS-Cov-2 antispike IgG S1/S2/RBD Diasorin), with a positive value >33.8 binding antibodies units (BAU)/mL (range of linearity 0–2,080 BAU/mL); total antinucleocapsid antibodies were measured by electrochemiluminescence with the Roche qualitative test; (2) the variation of CD4 count at baseline (before vaccination, T0) and after the second (T1) and the third vaccine dose (T2); (3) the percentage variation of PLWH with HIV-RNA <50 copies/mL at baseline (before vaccination, T0) and after the second (T1) and the third vaccine dose (T2); (4) the variation of antispike levels, CD4 counts, and HIV-RNA levels according to the occurrence or not of asymptomatic/paucisymptomatic COVID-19 infections, determined by positive antinucleocapsid Ab. HIV-RNA was measured with the COBAS Roche 6800 qualitative–quantitative real time-PCR method, with a limit of determinability of 20 copies/mL.

Other variables of interest included in the study were as follows: demographical data (age, gender, origin); risk factor for HIV acquisition; clinical data (CDC classification, AIDS event in medical history, years of HIV/AIDS, being on ART).

Statistical methods

Statistical differences among frequencies, percentages, and median were calculated with the chi-square test or with the Mann–Whitney U-test, as appropriate, using a significance level of 0.05. Data were analyzed using the free PSPP software.

Results

On the basis of inclusion criteria, 235 PLWH participated in the study. Data after the second dose of BNT162b2 were available for all patients. Data after third dose were available for 156 PLWH. Demographical, epidemiological, and clinical data at baseline are summarized in Table 1.

Table 1.

Demographical, Epidemiological, and Clinical Characteristics of 235 Persons Living with HIV Who received COVID-19 Vaccination with BNT162b2 at “D. Cotugno” Vaccination Facility, Naples

N° of patients	235
Age (median; IQR)	51; 14
Male gender (n; %)	214; 91.0
Italian origin (n; %)	219; 93.2
Risk factor for HIV acquisition
Etherosex (n; %)	62; 26.4
MSM (n; %)	98; 41.7
Use of injective drugs (n; %)	43; 18.3
Not known/not determined (n; %)	32; 13.6
Years of HIV (median; IQR)	8; 11
Previous AIDS events
Yes (n; %)	76; 31.1
No (n; %)	117; 49.8
Not known (n; %)	45; 19.1
Nadir CD4 (median; IQR)	222; 297
CD4 count at baseline (before first vaccination dose; median; IQR)	663; 448
CD4/CD8 ratio at baseline (before first vaccination dose; median; IQR)	0.90; 0.7
HIV-RNA in the 2 years before vaccination (data available for 155 pts)
Always <50 (n; %)	105; 67.7
At least one record 50–200 (n; %)	34; 21.9
At least one record >200 (n; %)	16; 10.3
On ART (n; %)	235; 100
Type of ART
INI-based triple regimen (n; %)	114; 48.5
PI-based triple regimen (n; %)	43; 18.3
NNRTI-based triple regimen (n; %)	30; 12.8
Two drugs regimen (n; %)	31; 13.2
Other (n; %)	17; 7.2

ART, anti-retroviral therapy.

The determination of antispike Ab forSARS-CoV-2 is performed for 187 and 64 PLWH after the second and third dose, respectively: PLWHs producing antispike >33 BAU/mL increase from 91% to 98%, with 36% and 71% of subjects with values out of upper level of linearity range (>2,080 BAU/mL). The average antispike value increased from 1,140 after the second dose to 1,848 BAU/mL after the third dose. The correlation between CD4 count and vaccine response can only be assessed after the second dose: among eight PLWHs with CD4 count <200 cells/μL, 25% did not produce antispike versus 5.6% among PLWH with CD4 > 200 cell/μL (p 0.0196). We assessed the effect of persistent HIV-RNA (HIV-RNA >50 copies/mL) on antispike Ab level; also, no correlations emerge among not-controlled HIV-RNA and level of antispike Ab response.

Antinucleocapsid Ab determination, performed in 147 and 56 patients, identified 19 (13%) asymptomatic/paucisymptomatic COVID-19 infections after the second dose and a further 15 (27%) after the third dose.

Virological and immunological variables of interest are summarized in Table 2. Data were collected: before the vaccine (T0, mean 87 days before); post-second dose (T1, mean 51 days after), and post-third dose (T2, mean 64 days after). The absolute number of CD4 increases after the third dose (median, interquartile range 663, 448; 657, 413; 707, 389 at T0, T1 and T2, respectively; T0 vs. T2 p < 0.000). CD4 percentage and CD4/CD8 ratio also increased after second and third dose, but not in a significant manner. The percentage of patients with HIV-RNA <50 copies/μL increases after the second and third dose, with significant difference between T0 and T2 (73%; 85.7%; 87.7%; T0 vs. T2 p < 0.023).

Table 2.

Immunological and Virological Changes Before and After Vaccination in 235 Persons Living with HIV Who Received COVID-19 Vaccination with BNT162b2 at “D. Cotugno” Vaccination Facility, Naples

	Before vaccination (T0, mean 87 days before, range 2–363) n: 235	After second dose (T1, mean 51 days, range 1–156) n: 235	After third dose (T2, mean 64 days, range 3–169) n: 155	Sig (p < 0.05) through Mann–Whitney U-test or chi-squared test as appropriate
CD4 cells/μL (median; IQR)	663; 448	657; 413	707; 389	T0 vs. T1 p: 0.5234 T0 vs. T2 p: <0.000 T1 vs. T2 p: 0.4809
CD4% (median; IQR)	33.8; 15	34.0; 15.5	34.3; 18	T0 vs. T1 p: 0.4718 T0 vs. T2 p: 0.7309 T1 vs. T2 p: 0.7357
CD4/CD8 ratio (median, IQR)	0.90; 0.7	0.90; 0.6	1.00; 0.8	T0 vs. T1 p: 0.5301 T0 vs. T2 p: 0.4542 T1 vs. T2 p: 0.4002
HIV-RNA (% of PLWH with <50 copies/μL)^a	73	85.7	87.7	T0 vs. T1 p: 0.1199 T0 vs. T2 p: 0.0226 T1 vs. T2 p: 0.2881

Significant values are in bold.

Data available for 155, 133, and 122 PLWH prevaccine, post-second dose, and post-third dose, respectively.

PLWH, persons living with HIV.

Table 3 summarizes the effect of asymptomatic/paucisymptomatic infection, determined by occurrence of antinucleocapsid Ab, on SARS-CoV-2 antispike Ab level, CD4 number, and HIV-RNA. Antispike Ab are significantly higher among those with natural infection after the second dose (p < 0.000), while this difference is not more significant after the third dose. Instead, there are no effects of asymptomatic/paucisymptomatic COVID-19 infection on CD4 and HIV-RNA.

Table 3.

Influence of Asymptomatic/Paucisymptomatic COVID-19 Infections on Vaccine Response, CD4 Number, and HIV-RNA Among 235 Persons Living with HIV Who Received COVID-19 Vaccination with BNT162b2 at “D. Cotugno” Vaccination Facility, Naples

	Before vaccination (T0, mean 87 days before) n: 235	PLWH without asymptomatic/paucisymptomatic infection after second dose (T1, mean 51 days after) n: 129	PLWH with asymptomatic/paucisymptomatic infection after second dose (T1, mean 51 days after) n: 19	PLWH without asymptomatic/paucisymptomatic infection after third dose (T2, mean 64 days after) n: 40	PLWH with asymptomatic/paucisymptomatic infection after third dose (T2, mean 64 days after) n: 15	Sig (p < 0.05) through Mann–Whitney U-test or chi-squared test
SARS-CoV-2 antispike Ab
n, % negative (<33.8 BAU/mL)		7; 5.7	0; 0	1; 2.7	0; 0	T1 yes^a vs. T1 no^a: p < 0.000
n, % positive (33.9–2,080 BAU/mL)		83; 68.0	2; 12.5	10; 27.7	2; 13.3	T2 yes^a vs. T2 no^a:
n, % positive (>2,080 BAU/mL)		32; 26.2	14; 87.5	26; 72.2	13; 86.6	p 0.633
CD4 cells/μL (median; IQR)	663; 448	639; 324	597; 331	632; 284	686; 207	T1 yes^a vs. T1 no^a: p 0.585T2 yes^a vs. T2 no^a: p 0.893
HIV-RNA (% of PLWH with <50 copies/μL)^a	73	87.5	89	87.5	90	T1 yes^a vs. T1 no^a: p 0.872T2 yes^a vs. T2 no^a: p 0.911

Significant values are in bold.

Yes: with positive antinucleocapsid Ab; no: with negative antinucleocapsid Ab.

BAU, binding antibodies units.

Discussion

PLWH on ART elicited satisfactory immunological response to COVID-19 after two doses and, even more satisfactory, after the third dose of BNT162b2 vaccine. These data are similar to those reported in other cohorts for this population (Brumme et al., 2021; Ruddy et al., 2021). As already suggested by other authors, in our population immunological response is lower among PLWH with <200 CD4 cells/μL, even if we were able to assess this correlation only after second dose, since immunological data among PLWH with low CD4 count after the third dose are available for one patient only (Antinori et al., 2022; Vergori et al., 2022). We also assessed the impact of not-controlled HIV-RNA (HIV-RNA >50 copies/mL) on vaccination response level, but no correlation emerged.

We performed, in a more limited number of patients, detection of antinucleocapsid Ab, to identify asymptomatic/paucisymptomatic infections: the number of infections not previously known by the patients increased from 13% to 27% after second and third dose, respectively. These findings are in line with general epidemiology of COVID-19 in Italy. Indeed, determination after second dose was performed mostly during 2021, whereas determination after third dose was performed mostly in 2022, during or after the peak of cases due to SARS-CoV-2 Omicron variants (Wordlometer, 2022).

As reported in the general population also, antispike Ab are significantly higher among those with natural infection. This effect is very evident and statistically significant, after the second dose, while this difference is not more significant after the third dose. We can argue that, in PLWH, the third dose is essential to reach an adequate level of immunity response, also among those with no natural infection. Instead, there are no effects of asymptomatic/paucisymptomatic COVID-19 infection on CD4 count and HIV-RNA level.

According to our data, vaccination with BNT162b2 has a positive impact on immunological markers among PLWH. Indeed, CD4 count increased in our population after vaccination, with an increased effect after the third dose. Similarly, the rate of PLWH with suppressed HIV-RNA increased after vaccination.

The transient increase of HIV-RNA reported after AS03-adjuvanted influenza vaccine exposure (Calmy et al., 2012) is not observed after BNT162b2 vaccination. On the contrary, we cannot attribute the virological and immunological improvements observed in our population to COVID-19 vaccination. Indeed, the general improvement observed may be due to natural evolution of an unselected population of PLWH on ART: the level of CD4 progressively increases for the expected improvement of CD4 count among recently diagnosed patients, while proactive and reactive ART switches to more effective therapies may positively influence HIV-RNA.

This study has several limitations. We did not include a control group of HIV-negative persons to compare the immunological response to vaccination. Moreover, only PLWH on ART were included, so conclusions cannot be generalized to entire population of PLWH. In addition, only one type of COVID-19 vaccine has been used, thus we cannot predict the response to other commercially available COVID-19 vaccines.

Conclusions

Despite these limitations, some interesting conclusions can be drawn from the findings of this study. PLWH regularly on ART and routinely followed up in a specialized center show a good antispike response after complete cycle of COVID-19 vaccination with BNT162b2, with no impact, or positive impact, on virological and immunological markers in terms of HIV-RNA and CD4 counts.

Footnotes

Authors' Contributions

F.M.F. contributed to conceptualization, methodology, analysis, investigation, and writing original draft; M.A.C. assisted with methodology, validation, investigation, writing—review and editing; N.S. and R.F. designed software, investigation, data curation, and writing—review and editing; M.D.A., O.T., F.B., R.V., C.C., V.B., R.P., G.P., V.R., P.R., and N.C. performed data curation, writing—review and editing; M.S., V.E., and V.S. contributed to conceptualization, resources, supervision, and writing—review and editing.

Ethics Approval Statement

Due to the observational nature of the study and the presentation of anonymized aggregated data only, no specific ethic approval is needed.

Patient Consent Statement

For all patients, a generic authorization is obtained to use, exclusively anonymously and collectively, data deriving from clinical practice. This article presents overall data, completely anonymous, from which it is not possible in any way to trace the identity of the subjects involved.

Data Sharing Statement

Original DB is available for review, upon request.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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