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.