Mixed outcomes following a third SARS-CoV-2 vaccine dose in previously unresponsive people with HIV

Dear Editor,

In the continuing SARS-CoV-2 pandemics, protecting immunocompromised populations is a top priority. Vaccination is key to worldwide healthcare strategies; the standard course involves two baseline injections followed with a first booster dose at six months. However, effective immunization may require additional doses and vaccination may even fail to elicit immunity in fragile populations [1,2]. People living with HIV (PLWH) are not enlisted as “at-risk” despite well-known HIV-related immune alterations and increased COVID-19 mortality [3]. Large vaccine trials did include some PLWH with normal CD4+ T-cell counts on antiretroviral therapy and vaccine efficiency was reportedly unchanged in these participants. However, studies by our group and others described impaired seroconversion rates and low anti-SARS-CoV-2-spike IgG titers following primary two-dose vaccination in PLWH with decreased CD4+ T-cell counts [4,5].

We report inconsistent antibody responses to a booster third vaccine dose in non- and low-responder PLWH (anti-SARS-CoV-2-Spike IgG titer <260 BAU/mL [6] after two injections, n = 38) from a previous study in adult PLWH [4]. Over the December 2021 – April 2022 period, 28 of 38 participants agreed to receive a third dose (booster) of vaccine (BNT162b2 or mRNA-1273). Four contracted COVID-19 with mild symptoms before providing serum samples, and one asymptomatic participant with post-infection anti-SARS-CoV-2-Capsid (N) antibodies was excluded. Twenty-three participants with post-boost anti-SARS-CoV-2-Spike (S) antibody titers and no history of COVID-19 were included: 70% were male, the median age was 56 years (interquartile range (IQR) 53–67) and the median CD4+ T-cell count was globally improved on antiretroviral therapy from 386 cells/µl at primary vaccination to 556 cells/µl at the time of the study (Table 1 ). Thirteen of 23 (56%) were initially vaccinated with CD4+ T-cell counts less than 500 cells/µl; they were 7 (30%) at booster vaccination.

Table 1.

Participant characteristics.

	Primary 2-dose vaccination	Booster third dose	p
n	23		-
Male: n (%)	16 (70%)		-
Comorbidities (hypertension, diabetes, respiratory disease, BMI>30kg/m2): n(%)	10 (43.5%)		-
Age at booster dose: yr [IQR]	56.0 [52.9–66.8]		-
Time since HIV diagnosis, at booster dose: yr [IQR]	25.4 [10.5–30.8]		-
Vaccine (n): BNT162b2/mRNA-1273/ChAdOx1-nCoV19	15/3/5	18/5/0	-
On a prescription of antiretroviral therapy when vaccinated: n (%)	22 (96%)	23 (100%)	-
CD4+ T-cells /µL: n [IQR]	386 [217–585]	556 [286–726]	0.01
Months since last immunization at anti-Spike IgG quantification: n [IQR] (Min / Max)	2.7 [1.87–3.43] (0.33 / 4.9)	2.4 [1.63–3.0] (0.67 / 4.5)	0.38
Anti-Spike IgG antibodies: median BAU/mL [IQR]	89.0 [47.4-169]	387.3 [242–1816]	<0.0001
Anti-Spike antibodies <260 BAU/mL: n (%)	23 (100)	6 (26.1)	<0.0001

n: number, BMI: body mass index, IQR: interquartile range, yr: years, BAU: normalized binding antibody units. Distributions were compared with the Mann-Whitney, Wilcoxon and Chi2 tests.

Booster shots were received 6 months after primary immunization (IQR: 5.5–7.0). The overall anti-SARS-CoV-2-Spike IgG titer at 2.4 months (IQR: 1.7–3) after the booster was 387 BAU/mL (IQR: 251–1749). In the 7 participants with CD4+T-cell counts less than 500/µl it was 356 (IQR: 37–1817). Antibody titers were generally improved by the boost (Fig. 1 ). However, 6 of 23 participants (26%) still did not achieve the putative protection threshold of 260 BAU/mL [6] after the third shot. They were not older than responders (median age 55.8 years, p = 0.72) and 5 of 6 had increased CD4+T-cells counts since dose 2. The two participants with 5 and 40 BAU/mL (80-year-old with 322 CD4+T-cells/µl and 58-year-old with 15 CD4+T-cells/µl, respectively) contracted the Omicron variant and died of COVID-19 despite ICU care.

Fig. 1.

Anti-SARS-COV-2-Spike IgG titers following booster vaccination in low-responder people living with HIV.

Specific anti-SARS-CoV-2-Spike IgG antibodies were quantified in 23 participants in normalized binding antibody units (BAU) (Architect SARS-COV-2 IgG II Quant, Abbott, USA) after vaccine dose 2 and after vaccine dose 3. Open circles: CD4+ T-cell count < 500/µL; black dots: CD4+ T-cell count > 500/µL. Cross symbols: COVID-19 deaths. Dotted line: putative protection threshold of 260 BAU/mL[6]. The 23 included samples tested negative for anti-SARS-CoV-2-N protein antibodies (Architect SARS-COV-2 IgG Assay, Abbott).

In this group of primary non- and low-responders to the standard 2-dose immunization, a booster dose increased anti-SARS-CoV-2-Spike antibody titers in most participants. This result emphasizes the importance of booster doses, including for patients previously unresponsive and who might lose interest in receiving extra shots. Among 7 cases of breakthrough SARS-COV-2 infections in the Delta/Omicron wave after three doses of vaccine, five exhibited no or mild symptoms. However, two persistent non-responders, with low CD4 T-cell counts, died of COVID-19.

These observations highlight the inconsistency of vaccine-induced SARS-CoV-2 immunity in PLWH, particularly with decreased CD4+ T-cell counts (participants with CD4+T-cells <500/µl: 356 (IQR 37-1817) BAU/mL anti-Spike IgG). Such outcomes in fragile patients support post-immunization serological testing and additional vaccine challenges and/or immunotherapy in unresponsive PLWH, along with efforts towards HIV care programs in regions with high HIV prevalence and susceptibility to prolonged and severe SARS-CoV-2 infections.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.