Hepatitis B Vaccine Response Holds Steady in Children with G6PD Deficiency, Study Finds

A common inherited enzyme deficiency does not appear to blunt the protective immune response to the hepatitis B vaccine in young children, according to a comparative cross-sectional study conducted in Heyuan, in China’s Guangdong province, and published in BMC Pediatrics. The research, led by Zhiqiang Ou of the Guangdong Institute of Biological Products and Drugs together with colleagues at several Chinese public health institutions, compared the persistence of antibodies against the hepatitis B surface antigen in children with glucose-6-phosphate dehydrogenase (G6PD) deficiency and in healthy controls. The findings offer reassurance to families in regions where G6PD deficiency is widespread, but the authors are careful to stress that their design cannot settle questions of vaccine safety in this population definitively.

G6PD deficiency is one of the most common enzymopathies in the world, affecting an estimated hundreds of millions of people, with particularly high prevalence in parts of Africa, the Mediterranean, the Middle East, and southern and eastern Asia. The condition arises from mutations in the gene encoding glucose-6-phosphate dehydrogenase, an enzyme critical to the pentose phosphate pathway that protects red blood cells from oxidative damage. Individuals with the deficiency are typically asymptomatic but can experience acute hemolytic anemia when exposed to certain drugs, infections, fava beans, or other oxidative stressors. Because vaccination involves an immune stimulus and, in some contexts, mild oxidative stress, researchers have long wondered whether children with G6PD deficiency might respond differently to routine immunizations, either in terms of antibody production or in terms of adverse reactions.

Hepatitis B vaccination is a cornerstone of global infant immunization programs. The vaccine works by presenting the hepatitis B surface antigen, a purified viral protein, to the immune system, prompting the generation of antibodies known as anti-HBs. A concentration of at least 10 milli-international units per milliliter is conventionally regarded as the threshold of seroprotection, meaning the child is considered protected against chronic hepatitis B virus infection. Antibody levels wane over time in many vaccinated individuals, but immune memory generally persists, and the durability of the initial response is an important indicator of how well a vaccine schedule is performing in a given population. Whether G6PD status alters this durability had not been rigorously examined in young children before this study.

The research team enrolled 505 children in Heyuan between March 2024 and January 2025, of whom 55 had enzymatically confirmed G6PD deficiency and 450 served as controls. The control group was frequency-matched by sex, and body mass index was used to balance the groups at the group level. Nearly all participants, 98.2 percent, were between one and four years of age, an age window chosen because it captures children who have completed the primary hepatitis B vaccine series but are still within the period when maternal and early childhood factors can be reasonably accounted for. Vaccination histories were drawn from official immunization records rather than parental recall, a methodological choice that strengthens the reliability of the exposure data.

The primary analysis focused on antibody persistence and included only children whose blood was sampled at least six months after the third dose of the hepatitis B vaccine, yielding 54 children with G6PD deficiency and 438 controls. The mean interval between the third dose and sampling was approximately 30 months, meaning the study was measuring how well vaccine-induced antibodies had held up over two and a half years on average. Anti-HBs concentrations were measured at enrollment using a chemiluminescent microparticle immunoassay, a sensitive and widely standardized laboratory technique for quantifying specific antibodies in serum.

The headline result was strikingly reassuring. Seroprotection, defined as an anti-HBs level of at least 10 mIU/mL, was observed in 87.0 percent of children with G6PD deficiency compared with 82.2 percent of controls. The unadjusted risk difference was 4.8 percentage points, with a 95 percent confidence interval spanning from minus 7.1 to plus 12.4 percentage points, and the adjusted risk ratio was 1.07 with a confidence interval of 0.96 to 1.19. In other words, the point estimate slightly favored the G6PD-deficient group, but the confidence interval comfortably included the null value of no difference, so the authors could not rule out either a modest benefit or a modest disadvantage. When the researchers modeled the logarithmically transformed antibody concentrations directly, adjusting for age, sex, body mass index, time since the third dose, and vaccine product, the association with G6PD deficiency was essentially flat, with a beta coefficient of minus 0.04 and a p-value of 0.90.

The team also examined whether parents reported more post-vaccination symptoms in children with G6PD deficiency. Parents were asked retrospectively about six common symptoms occurring within 30 days after each hepatitis B vaccine dose. At least one symptom was reported for 5 of the 55 children with G6PD deficiency, or 9.1 percent, compared with 19 of 450 controls, or 4.2 percent, a difference that was not statistically significant with a p-value of 0.17. The numerical trend toward more reported symptoms in the G6PD group is worth noting, but with such a small number of affected children and a retrospective design, the authors rightly declined to interpret it as evidence of a real safety signal.

The statistical machinery behind these comparisons deserves attention. The researchers used modified Poisson regression with robust standard errors to estimate risk ratios for binary outcomes such as seroprotection, an approach that has become standard in epidemiology because it avoids the rate-inflation problems that can arise when logistic regression is applied to common outcomes. Linear regression on log-transformed antibody concentrations allowed them to assess differences in the geometric mean concentration while accommodating the right-skewed distribution typical of antibody titers. All models were adjusted for age, sex, body mass index, the elapsed time since the third vaccine dose, and the specific vaccine product used, each of which could plausibly influence antibody persistence independently of G6PD status.

Despite the reassuring point estimates, the authors are explicit that their study does not establish equivalence between the two groups. Equivalence testing requires pre-specified margins and adequate statistical power, neither of which this study was designed to deliver, and the small number of children with enzymatically confirmed G6PD deficiency limits the precision of every estimate. The retrospective reporting of post-vaccination symptoms is a further constraint: parents were asked to recall events that in many cases had occurred years earlier, and the long recall interval introduces the possibility of differential misclassification, particularly if parents of children with a known diagnosis pay closer attention to symptoms. The study also did not systematically ascertain hemolysis-related outcomes or serious adverse events, which are the outcomes of greatest theoretical concern in G6PD deficiency, so no conclusions can be drawn about G6PD-specific vaccine safety from these data.

Looking forward, the authors call for larger prospective multicenter cohorts that incorporate genetic typing of G6PD variants, quantitative measurement of G6PD enzyme activity, standardized serological follow-up at defined intervals, and active safety surveillance rather than parental recall. Such studies would allow researchers to distinguish among the many genotypes that produce G6PD deficiency, some of which are associated with far more severe enzyme reduction than others, and to detect rare adverse events that no single-center study can capture. In the meantime, the study provides the most direct evidence to date that the standard hepatitis B vaccine series induces comparable seroprotection in young children with and without G6PD deficiency, a finding that supports current immunization practice in the many regions of the world where this enzyme deficiency and hepatitis B overlap geographically. The work was supported by the China Hepatitis B Prevention and Control Research Fund of the China Hepatitis Prevention Foundation, and the full open-access article is available in BMC Pediatrics.

Subject of Research: Antibody persistence after hepatitis B vaccination in young children with G6PD deficiency

Article Title: Persistence of antibody to hepatitis b surface antigen and reported post-vaccination symptoms in young children with glucose-6-phosphate dehydrogenase deficiency: a comparative cross-sectional study

Article References: Persistence of antibody to hepatitis b surface antigen and reported post-vaccination symptoms in young children with glucose-6-phosphate dehydrogenase deficiency: a comparative cross-sectional study. (n.d.). https://doi.org/10.1186/s12887-026-07807-1

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07807-1

Keywords: G6PD deficiency, hepatitis B vaccine, antibody persistence, seroprotection, children, post-vaccination symptoms, cross-sectional study, anti-HBs, vaccine immunogenicity, China, pediatrics, adverse events