DISCUSSION
Studying immunogenicity to COVID-19 vaccines enables us to understand protection conferred by vaccination on IEI patients. Three doses of BNT162b2 and CoronaVac were well-tolerated by our pediatric and adult IEI patients. Antibody responses to COVID-19 vaccines were found to be lowest in patients with humoral deficiencies, yet non-responders were also found in other IEIs not affecting adaptive immunity. Antibody responses were enhanced by a third dose of vaccine, especially cross-neutralization against SARS-CoV-2 variant Omicron. T cell responses were detected in many patients after vaccination, yet there is heterogeneity in responses. Patients who received intradermal vaccination appeared in general to have higher antibody levels but had similar T cell response, though sample sizes were small. Breakthrough infections with BA.2 were mild in vaccinated IEI patients.
Antibody responses were a primary outcome measured in many COVID-19 vaccine studies, including this study, as antibody responses have been shown to correlate with protection against symptomatic COVID-19.26 Our finding of seroconversion failure in 45% patients after 2 doses of COVID-19 vaccines, which was reduced to 26% after a third dose, strongly support the need for a 3-dose primary series in patients with IEIs. Another study also found seroconversion failure was reduced from 39% to 24% after a third dose in a heterogeneous cohort of IEI patients with mostly humoral immunodeficiencies.27 Many of these IEI patients, especially those with humoral deficiencies, mounted a detectable T cell response to COVID-19 vaccines. While understudied and controversial in the virology and vaccinology fields,28 adaptive immunity against severe viral illnesses, except for enteroviruses, depends on T cells rather than B cells, as exemplified by recurrent and life-threatening viral infections in patients with combined immunodeficiencies but not in those with agammaglobulinemia.29 The presence of both common seroconversion and T cell response in triple-vaccinated IEI patients suggests 3 doses may be adequate for primary series in IEI patients in general. A fourth dose is likely required a few months after the primary series as a booster, dependent on circulation of SARS-CoV-2 in the community, degree of antibody waning, and potency of cellular memory.
Although numbers of participants in each IEI category was small, trends could be observed. For example, those with humoral immunodeficiencies developed the lowest S-RBD IgG and sVNT after 2 vaccine doses, seroconversion failure was also found in a patient with STAT1gain-of-function after 2 doses and another with SCN after 3 doses of vaccine as well. Both patients did not undergo HSCT, and neither was on immunosuppressive medications. While functional antibody deficiency is known to associate with STAT1gain-of-function,30 impairment of humoral immune response in phagocytic disorders is not well delineated. Within our study, 5 out of 6 enrolled patients with phagocytic disorders (2 with SCN, 2 with chronic granulomatous disease, CGD, and 1 X-linked CGD carrier) did not seroconvert to a single dose of BNT162b2 (n=3) or a single dose of CoronaVac (n=2), which contrasts with the 100% seroconversion to a single dose of BNT162b2 in healthy adolescents.15 Our findings suggest a partially impaired B cell response to vaccines in patients with phagocytic disorders, which may be rescued by dose 2 or more additional doses. While conventional knowledge dictates vaccine response may only be impaired in patients with adaptive defects, seroconversion failure may be found in patients with different IEIs, and patients with any specific IEI should be recommended to complete the 3-dose primary series with booster vaccination, irrespective of disease category.
CoronaVac is widely used globally, and this is likely to include patients with IEI patients as well, yet little data have been published on IEI patients. Studies in adult patients with secondary immunodeficiencies or immune dysregulation disorders showed reduced antibody responses to 2 doses of CoronaVac.31-33 S-RBD IgG and sVNT results in our study showed 3 doses of CoronaVac elicited antibody response in IEI patients. Eleven of 17 patients with humoral deficiencies in our study opted for CoronaVac. Whole-virion inactivated vaccines could elicit T cell response against other structural proteins such as N and M unelicited by S-only mRNA vaccines,15,34 which correlate with protection against severe disease and infection,35,36 and are not susceptible to mutations in Omicron.24 In our patients with humoral immunodeficiencies and no breakthrough COVID-19, 4 out of 5 patients in our study had a detectable SNM-specific IFN-γ+ CD4+ T cell response after just 2 doses of CoronaVac; the single patient who did not have a detectable IFN-γ+ CD4+ T cell response had an IL-2+ CD4+ T cell response. The effectiveness of CoronaVac in IEI patients was further supported by the 4 patients who received CoronaVac and experienced a mild breakthrough COVID-19. Our results support that CoronaVac is safe and effective in IEI patients.
We hypothesized intradermal vaccination may elicit better antibody and T cell responses in IEI patients. While there seemed to be no appreciable difference with T cell response of intradermal vaccination in IEI patients, we found a trend toward higher antibody responses in intradermal vaccinees. Additional studies involving healthy children or IEI patients may confirm our findings. We also examined the immunogenicity outcomes in patients receiving intradermal vaccination on a case-by-case basis as “n-of-1 trials”. Strikingly, one patient, who is a 15-year-old boy with post-HSCT X-SCID, did not seroconvert after receiving 3 doses of intradermal CoronaVac and contracting COVID-19 during the Omicron BA.2-dominant period in Hong Kong. Chart review revealed that the patient had a successful allogenic hematopoietic stem cell transplant with a 10/10 matched unrelated donor and conditioning regimen of fluradabine, melphalan, anti-thymocyte globulin and rituximab by the age of 1 year, resulting in 51% donor chimerism in the peripheral blood and him being generally healthy without immunoglobulin replacement. Last follow-up showed normal T and B cell counts (1829 cells/ul and 406 cells/ul) and normal IgG level (1289 mg/dl). The patient also previously seroconverted to intramuscular vaccines with seropositivity for measles, mumps, rubella, and tetanus. He has been on penicillin prophylaxis after splenectomy at age of 1 year as disseminated BCGosis involved his spleen. Interestingly, 2 years prior to COVID-19 vaccination, the patient developed cryotherapy-resistant verruca vulgaris on his right hand, a known complication after HSCT in X-SCID patients. That led us to hypothesize that seroconversion failure to intradermal vaccine is also due to mutated keratinocytes in the skin, with impaired chemotactic functions, not corrected by HSCT.37,38 This finding suggests that while intradermal vaccination may enhance seroconversion in most immunocompromised vaccinees, X-SCID patients who underwent HSCT may not benefit from intradermal vaccination.
Our study had several strengths and limitations. In addition to antibodies, we also studied T cell responses, which protect against disease progression. We were able to track both antibody and T cell responses sequentially in vaccinees from pre-vaccine to post-dose 3. The utility of longitudinal antibody testing in predicting infections deserves to be studied in larger multi-cohort studies. Our sample size was limited due to rarity of IEIs, yet studies from other centers could corroborate our findings. We could not assess clinical effectiveness.
In conclusion, our findings support the need for 3 doses of mRNA or inactivated COVID-19 vaccines for IEI patients and this should be regarded as the primary series of vaccination. Future studies should focus on the longevity of immune response and effect of a fourth dose and hybrid immunity in these patients.