Study: Comprehensive antibody profiling of mRNA vaccination in children. Image Credit: aslysun/ Shutterstock

Vaccinated children induced significantly higher antibody titers than naturally SARS-CoV-2 infected children


A recent preprint available on the bioRxiv* preprint server discusses the antibody response to the nucleic acid vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) when administered to children aged 7-11 years.

Study: Comprehensive antibody profiling of mRNA vaccination in children. Image Credit: aslysun/ ShutterstockStudy: Comprehensive antibody profiling of mRNA vaccination in children. Image Credit: aslysun/ Shutterstock

Background

As SARS-CoV-2 spread rapidly worldwide, scientists responded with unprecedented efforts to develop effective vaccines.

With high rates of morbidity and mortality among the older population and those with underlying comorbidities, vaccine rollouts were prioritized to these groups at first and frontline essential workers.

However, many groups were left at risk of infection and being able to drive community transmission. This includes children who have not had high rates of symptomatic coronavirus disease 2019 (COVID-19) but can harbor the virus at high loads and help to transmit the virus.

With schools being reopened, children are developing COVID-19 at higher rates. This has led to an increasing number of severe cases in this age group, with a small minority developing complications such as the Multisystem Inflammatory Syndrome in Children (MIS-C).

This led to an increasing perception that children should also receive the vaccine. One area of uncertainty has been how this group would respond to these vaccines, with their relatively naïve immune system.

The current study explored the immune response in children vaccinated with two 100μg doses of the mRNA-1273 (from Moderna) vaccine. The median age of the group was nine years.

The three time points selected for the study of the antibody response were before vaccination, and four weeks from the first and second doses, respectively. These are represented as V0, V1, and V2.

What did the study show?

The researchers found that the vaccination led to the generation of immunoglobulin (Ig) antibodies, namely IgM, IgA, and IgG1 binding antibodies, at V1, targeting the viral spike. The IgA1 and IgG1 antibody titers rose significantly at V2, but anti-spike IgM dropped, albeit only a little. This indicates that class-switching proceeded as required.

IgM and IgA1 antibodies to the spike were reduced, but IgG1 binding antibodies were higher at V2 compared to adults at the same time point. At both V1 and V2, vaccine-elicited antibodies were higher than those observed in children with acute COVID-19 or with MIS-C.

Neutralizing antibodies were detected after the priming dose. They rose further after the booster dose in all vaccinated children, to levels equivalent to or higher than in adults and higher than those in naturally infected children.

This agrees with studies that show antibody isotypes shifting with age, with the IgG response being more prominent in children but a broader response in adults. The implications of this may be that children are more prone to contract mucosal infections, including influenza and respiratory syncytial virus.

To counteract this, vaccines intended for children may have to be modified to enhance mucosal immunity via IgA antibodies.

In adults, protection against severe COVID-19 depends on antibody effector functions such as cytotoxic and opsonin-mediated phagocytosis. This aspect was explored in this study.

This involves antibody binding to Fc-receptors. It also induces antibody-dependent complement deposition (ADCD), antibody-dependent neutrophil phagocytosis (ADNP), antibody-dependent monocyte phagocytosis (ADCP), or activation antibody-dependent NK cell activation (ADNKA).

The results show that the vaccine in children also led to anti-spike IgG antibodies that bound strongly to all the Fcγ receptors after the priming dose, compared to the response after natural infection. This binding response was boosted after the second dose.

The IgA-FcαR binding antibodies were reduced in vaccinated children relative to adults, as expected from lower IgA levels in children.

Vaccine-induced effector functions in children were also examined. These were variable, with ADCD and ANDP occurring at levels comparable to those in adults after the booster dose, though the priming dose-response was low.

ADCP was higher after the priming dose, and after the booster dose, it became still higher, exceeding adult levels. The activation of natural killer (NK) lymphocytes seen in a subgroup of adults was seen at slightly lower levels in children following vaccination.

Binding antibodies to different domains of the spike antigen followed similar response patterns independent of age. This suggests that other factors, such as the glycosylation pattern of the antibody Fc could drive the higher antibody response in children rather than a difference in the binding profile.

Further analysis using a machine-learning approach indicates that many features of vaccine-induced functional immunity were higher in children. The strong FcγR binding capacity drove this and Fc mediated phagocytosis in children.

Overall, children showed a broader and stronger Fc-receptor binding profile than adults, while the latter showed a higher NK cell/IgA response.

Currently, it is supposed that children, with their naïve immune repertoire, respond to new pathogens more flexibly and broadly due to the production of naïve immune cells by the thymus and bone marrow. In this case, binding titers for all SARS-CoV-2 variants of concern were lower in children than the wild-type spike, as well as for FcγR binding, mirroring those in adults.

The neutralizing responses to the wild-type variant were identical in children and adults but markedly lower against the Delta variant in children compared to adults.

Nonetheless, it is noteworthy that the sera from vaccinated children robustly neutralized ancestral and Delta strains of the virus, as well as a preferential expansion of ADNP and ADCP in children against both variants.

What are the implications?

The results show that vaccination with the mRNA vaccine in children elicits higher antibody titers and effector functions than those found after natural infection. The protection extended across variants of concern of SARS-CoV-2.

Children appeared to respond to the vaccine with higher Fcγ-receptor binding and phagocytic antibodies than adults. The lower response to Delta may indicate the need to incorporate pooled antigens or use a heterologous vaccine regimen. This could ensure a broader response covering not only variants of SARS-CoV-2 but also other emerging coronavirus pathogens.

The vaccine-induced immunity to the variants of concern exceeded that elicited by natural infection. Moreover, children may use antibody effector functions to protect themselves against the virus rather than relying on neutralizing antibodies alone.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.



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