Acute COVID-19 and vaccinations induce cross-reactive antibody responses in breast milk

As of June 28, 2022, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), has infected over 545 million people and caused over 6.3 million deaths worldwide caused.

To learn: Broad cross-reactive IgA and IgG against human coronaviruses in milk induced by COVID-19 vaccination and infection. Photo credit: evso / Shutterstock.com

Cross-reactive immunity against SARS-CoV-2

SARS-CoV-2 shares sequence homologies with immunodominant epitopes found on the spike protein of several other human coronaviruses (HCoVs). More specifically, the S2 subunit of SARS-CoV-2 shares a greater degree of sequence homology with HCoV strains compared to the S1 subunit.

Individuals suffering from symptomatic COVID-19 often produce a variety of SARS-CoV-2 antibodies, the robustness of which correlates directly with the severity of the disease. Previous studies have also indicated that the early humoral response to SARS-CoV-2 is mediated by pre-existing OC43-reactive antibodies produced following infection with other HCoVs.

A major source of pre-existing immunity to emerging SARS-CoV-2 variants is antibody cross-reactivity due to infection with earlier virus strains. This cross-reactive immunity is similar to that which could be achieved after immunization against a new SARS-CoV-2 strain against previously circulating strains.

SARS-CoV-2 antibodies in breast milk

Infants often receive protection from various infectious diseases by exposure to maternal immunoglobulins (Igs), which are present in human breast milk. To this end, previous studies have found that secretory anti-SARS-CoV-2 IgA is present in human breast milk both during and after acute infection and that these antibodies are able to neutralize SARS-CoV-2 in vitro.

In addition, breast milk from mothers receiving topical messenger ribonucleic acid (mRNA) COVID-19 vaccines also appears to contain high levels of IgA and IgG, which are capable of neutralizing SARS-CoV-2. Importantly, the milk of breastfeeding mothers infected with SARS-CoV-2 does not appear to transmit the virus to the nursing infant.

Previous reports have failed to demonstrate the protection that pre-pandemic human breast milk samples conferred against the SARS-CoV-2 receptor-binding domain (RBD) present in the spike protein. However, there is still a limited amount of data on whether breast milk from mothers who have recovered from and/or been vaccinated against COVID-19 contains antibodies that are cross-reactive with other HCoVs.

About the study

In a recent vaccinations study examined anti-spike and anti-N-terminal domain (N) IgA and IgG in human breast milk and blood for their activity against SARS-CoV-2 and SARS-CoV-1, as well as four other prevalent HCoVs including 229E , OC43, NL63 and HKU1 after the breastfeeding mothers were vaccinated against or recovered from COVID-19.

Study cohorts and experimental design.  This prospective study consists of two cohorts: (A) The vaccinated cohort included nursing parents (n=30) who were older than 18 years with no history of COVID-19 infection and who were either Pfizer-BioNTech/BNT162b2 or Moderna/mRNA- 1273 mRNA should receive vaccination.  Human milk and fingerstick blood samples were collected prior to vaccination and 18 days after the first and second doses.  (B) The infection cohort included nursing parents who had received an RT-PCR COVID-19 diagnosis within the past 14 days.  Breast milk samples were collected on admission day 0, then on days 3, 10, 19 and 28.  Fingerstick blood samples were collected on days 0 and 28.Study cohorts and experimental design. This prospective study consists of two cohorts: (A) The vaccinated cohort included nursing parents (n=30) who were older than 18 years with no history of COVID-19 infection and who were either Pfizer-BioNTech/BNT162b2 or Moderna/mRNA- 1273 mRNA should receive vaccination. Human milk and fingerstick blood samples were collected prior to vaccination and 18 days after the first and second doses. (B) The infection cohort included nursing parents who had received an RT-PCR COVID-19 diagnosis within the past 14 days. Breast milk samples were collected on admission day 0, then on days 3, 10, 19 and 28. Fingerstick blood samples were collected on days 0 and 28.

A total of 46 breastfeeding mothers previously infected with SARS-CoV-2, as confirmed by a reverse transcription polymerase chain reaction (RT-PCR) test, were enrolled in the current study. Milk samples were collected from these mothers on days zero, three, seven, ten and twenty-eight.

In addition, a total of 30 breastfeeding mothers who received either the Pfizer-BioNTech BNT162b2 or Moderna mRNA-1273 COVID-19 vaccine were enrolled in the current study. Both milk and finger samples were collected from these participants prior to vaccination and 18 days after receiving both the first and second doses of vaccine.

study results

Compared to pre-vaccination levels, IgA and IgG levels against total SARS-CoV-2 spike protein, S1, S2 and RBD subunits were significant in both breast milk 18 days after receiving the first dose of vaccine higher and blood. In fact, post-vaccination anti-spike IgA and IgG levels in breast milk samples increased consistently by 10- and 100-fold, respectively.

Breast milk and blood SARS-CoV-2-specific IgA and IgG antibody response to mRNA vaccination in nursing parents.  (A) IgA and IgG antibody responses to SARS-CoV-2 S (SARS2-S), S1, S2, RBD and N of SARS-CoV-2 elicited by COVID-19 mRNA vaccination.  Fingerstick milk and blood samples were collected before vaccination (PRE), 18 days after the first dose (Vac1) and 18 days after the second dose (Vac2).  Antibody concentrations were estimated using the mPLEX-CoV assay (see Methods).  Generalized mixed-effects linear models were used to test for differences between time points (****p<0.0001, ***p<0.001, **p<0.01, *p < 0,05).  (B) Heatmap der Spearman-Korrelationen zwischen IgA- und IgG-Konzentrationen gegen SARS2-S, S1, S2 und RBD in Milch und Blut.  Korrelationskoeffizienten (r) sind farbcodiert, wie in der Abbildung gezeigt, und numerische Werte werden angegeben, wenn der Korrelations-p-Wert kleiner als 0,005 ist.Breast milk and blood SARS-CoV-2-specific IgA and IgG antibody response to mRNA vaccination in nursing parents. (A) IgA and IgG antibody responses to SARS-CoV-2 S (SARS2-S), S1, S2, RBD and N of SARS-CoV-2 elicited by COVID-19 mRNA vaccination. Fingerstick milk and blood samples were collected before vaccination (PRE), 18 days after the first dose (Vac1) and 18 days after the second dose (Vac2). Antibody concentrations were estimated using the mPLEX-CoV assay (see Methods). Generalized mixed-effects linear models were used to test for differences between time points (****pB) Heatmap of Spearman’s correlations between IgA and IgG concentrations against SARS2-S, S1, S2 and RBD in milk and blood. Correlation coefficients (r) are color-coded as shown in the figure, and numerical values ​​are reported when the correlation p-value is less than 0.005.

Both breast milk anti-spike IgA and blood samples remained the same or decreased after receiving the second dose of vaccine. In comparison, IgG levels in both breast milk and blood increased up to 187 days after the second dose of vaccination, above levels observed after receiving the first dose. Anti-S2 IgG levels were not as high as anti-spike, S1, and RBD IgG levels.

Compared to pre-vaccination anti-spike IgA and IgG levels in nursing mothers, infected individuals had significantly higher levels of these antibodies. Both anti-N-IgA and IgG antibodies were also detected in the breast milk of infected mothers at levels that were constant throughout the course of their infection.

Both IgA and IgG levels were highly correlated between blood and breast milk samples from infected mothers. This coupled response appears to be accompanied by a mucosal response observed in breast milk from infected mothers that was not observed in breast milk from vaccinated mothers.

After the first and second doses of vaccine, anti-SARS-CoV-2 IgG levels in breast milk increased significantly, while IgA levels increased more slowly. After the first and second doses of vaccine, anti-SARS-CoV-2 IgG levels increased 163- and 780-fold, respectively, compared to pre-vaccination levels. In comparison, anti-SARS-CoV-2 IgA increased 5.21- and 2.11-fold at both time points, respectively.

The COVID-19 vaccination also resulted in a 0.43- to 6.04-fold increase in breast milk IgG antibodies to SARS-CoV-1, OC43, HKU1, 229E and NL63 HCoVs. However, this effect was not replicated in blood samples, where immunization produced no IgG against 229E and NL63, both of which are antigenically more diverse α-HCoVs, and instead only produced broadly reactive IgG against OC43 and HKU1.

Breast milk and blood samples obtained from infected mothers showed comparable cross-reactive IgA and IgG antibody binding patterns. While IgG levels increased 28.5- and 71.00-fold, respectively, on days 0 and 28 after COVID-19 diagnosis, IgA levels increased 7.15- and 5.56x.

Cross-reactive binding of IgA and IgG to the OC43 and HKU1-β-HCoVs spike proteins was broader and stronger in breast milk and blood samples from COVID-19 positive mothers compared to those generated by vaccination. IgG antibodies produced in human milk samples following SARS-CoV-2 infection showed a broader spectrum of cross-reactivity than human milk IgA and blood IgG, including reactivity against NL63 and 229E.

effects

The current study is the first to show that broad cross-reactive IgG and IgA antibodies against HCoVs in human breast milk were produced by both COVID-19 mRNA immunization and prior SARS-CoV-2 infection. Overall, the results showed that acute COVID-19 elicited a broader cross-reactive antibody response against HCoV spike proteins in contrast to the two-dose mRNA vaccination schedule.

These results also indicate a strong association between post-infection peripheral blood and vaccination with anti-spike IgG in breast milk; however, no correlation was observed between milk and blood anti-spike IgA.

Magazine reference:

  • Wang J, Young BE, Li D, & Seppo A (2022). Broad cross-reactive IgA and IgG against human coronaviruses in milk induced by COVID-19 vaccination and infection. vaccinations. doi:10.3390/Vaccines10060980

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