WHO International Standard for evaluation of the antibody response to COVID-19 vaccines: call for urgent action by the scientific community

Knežević, Ivana; Mattiuzzo, Giada; Page, Mark; Minor, Philip D.; Griffiths, Elwyn; Nuebling, Micha; Moorthy, Vasee S.

doi:10.1016/s2666-5247(21)00266-4

Cited by 131 publications

(134 citation statements)

References 18 publications

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“…We have previously shown that although serum antibodies against the RBD of the S protein of SARS-CoV-2 are markedly reduced 6-12 months after infection, long-lived B and T cell memories persist for up to 15 months and may thus aid in resistance against re-infection 22,23 . Here, we show that the decline of the serum antibody levels was more rapid in the vaccinated individuals compared to naturally infected patients, supporting and extending previous findings 24, 25 . This raises the question on strategies for boosting the immune response in vaccine recipients, which is of particular concern in view of the limited induction of cross-neutralizing antibodies against the Omicron VOC even by the mRNA vaccines [26][27][28][29][30][31] .…”

Section: Discussionsupporting

confidence: 92%

Heterologous immunization with inactivated vaccine followed by mRNA booster elicits strong humoral and cellular immune responses against the SARS-CoV-2 Omicron variant

Zuo

Abolhassani

et al. 2022

Preprint

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Background There has been an unprecedented global effort to produce safe and effective vaccines against SARS-CoV-2. However, production challenges, supply shortages and unequal global reach, together with an increased number of breakthrough infections due to waning of immunity and the emergence of new variants of concern (VOC), have prolonged the pandemic. To boost the immune response, several heterologous vaccination regimes have been tested and have shown increased antibody responses compared to homologous vaccination. Here we evaluated the effect of mRNA vaccine booster on immunogenicity in individuals who had been vaccinated with two doses of inactivated vaccines. Methods The levels of specific antibodies against the receptor-binding domain (RBD) of the spike protein from wild-type virus and the Beta, Delta and Omicron variants were measured in healthy individuals who had received two doses of homologous inactivated (BBIBP-CorV or CoronoVac) or mRNA (BNT162b2 or mRNA-1273) vaccines, and in donors who were given an mRNA vaccine boost after two doses of either vaccine. Pre-vaccinated healthy donors, or individuals who had been infected and subsequently received the mRNA vaccine were also included as controls. In addition, specific memory B and T cell responses were measured in a subset of samples. Results A booster dose of an mRNA vaccine significantly increased the level of specific antibodies that bind to the RBD domain of the wild-type (6-fold) and VOCs including Delta (8-fold) and Omicron (14-fold), in individuals who had previously received two doses of inactivated vaccines. The level of specific antibodies in the heterologous vaccination group was furthermore similar to that in individuals receiving a third dose of homologous mRNA vaccines or boosted with mRNA vaccine after natural infection. Moreover, this heterologous vaccination regime significantly enhanced the specific memory B and T cell responses. Conclusions Heterologous prime-boost immunization with inactivated vaccine followed by an mRNA vaccine boost markedly increased the levels of specific antibodies and B and T cell responses and may thus increase protection against emerging SARS-CoV-2 variants including Omicron.

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Section: Discussionsupporting

confidence: 92%

Heterologous immunization with inactivated vaccine followed by mRNA booster elicits strong humoral and cellular immune responses against the SARS-CoV-2 Omicron variant

Zuo

Abolhassani

et al. 2022

Preprint

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“…Inhibition signal from individual samples from the cPass assay was converted to the World Health Organization (WHO) International Units (IU) based on previous calibration of this neutralization assay against the WHO International Standard (IS) for SARS-CoV-2 neutralization assays ( 21 , 22 ), using a Excel-based conversion tool available online ( ). Based on recent studies using biological replicates from different international groups, cPass readings (% inhibition) were shown to be highly reproducible to International Units (IU)/ml of the WHO International Standard, with a pseudo R 2 at 0.978. cPass inhibition signal of 30% corresponds to a cut-off of 28 IU/ml for serum samples and 7 IU/ml for breastmilk samples based on the conversion to WHO International Standard and dilution factor for sample type.…”

Section: Methodsmentioning

confidence: 99%

Section: Sars-cov-2 Surrogate Viral Neutralization Assaymentioning

confidence: 99%

Neutralizing Activity and SARS-CoV-2 Vaccine mRNA Persistence in Serum and Breastmilk After BNT162b2 Vaccination in Lactating Women

et al. 2022

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BackgroundThere is limited information on the functional neutralizing capabilities of breastmilk SARS-CoV-2-specific antibodies and the potential adulteration of breastmilk with vaccine mRNA after SARS-CoV-2 mRNA vaccination.MethodsWe conducted a prospective cohort study of lactating healthcare workers who received the BNT162b2 vaccine and their infants. The presence of SARS-CoV-2 neutralizing antibodies, antibody isotypes (IgG, IgA, IgM) and intact mRNA in serum and breastmilk was evaluated at multiple time points using a surrogate neutralizing assay, ELISA, and PCR, over a 6 week period of the two-dose vaccination given 21 days apart.ResultsThirty-five lactating mothers, median age 34 years (IQR 32-36), were included. All had detectable neutralizing antibodies in the serum immediately before dose 2, with significant increase in neutralizing antibody levels 7 days after this dose [median 168.4 IU/ml (IQR 100.7-288.5) compared to 2753.0 IU/ml (IQR 1627.0-4712.0), p <0.001]. Through the two vaccine doses, all mothers had detectable IgG1, IgA and IgM isotypes in their serum, with a notable increase in all three antibody isotypes after dose 2, especially IgG1 levels. Neutralizing antibodies were detected in majority of breastmilk samples a week after dose 2 [median 13.4 IU/ml (IQR 7.0-28.7)], with persistence of these antibodies up to 3 weeks after. Post the second vaccine dose, all (35/35, 100%) mothers had detectable breastmilk SARS-CoV-2 spike RBD-specific IgG1 and IgA antibody and 32/35 (88.6%) mothers with IgM. Transient, low intact vaccine mRNA levels was detected in 20/74 (27%) serum samples from 21 mothers, and 5/309 (2%) breastmilk samples from 4 mothers within 1 weeks of vaccine dose. Five infants, median age 8 months (IQR 7-16), were also recruited - none had detectable neutralizing antibodies or vaccine mRNA in their serum.ConclusionMajority of lactating mothers had detectable SARS-CoV-2 antibody isotypes and neutralizing antibodies in serum and breastmilk, especially after dose 2 of BNT162b2 vaccination. Transient, low levels of vaccine mRNA were detected in the serum of vaccinated mothers with occasional transfer to their breastmilk, but we did not detect evidence of infant sensitization. Importantly, the presence of breastmilk neutralising antibodies likely provides a foundation for passive immunisation of the breastmilk-fed infant.

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“…Indeed, in the current pandemic a large number of serological tests, based on different technologies and recognizing different epitopes of the S-protein, have been used along with neutralization assays. Even if an international standard for the evaluation of the antibody response to COVID-19 has been released by the WHO [13], its utility in enabling comparability of binding antibody tests has been criticized [14,15] and its use for standardization of neutralizing antibodies assays is still limited to few laboratories [13].…”

Section: Introductionmentioning

confidence: 99%

Differential Dynamics of SARS-CoV-2 Binding and Functional Antibodies upon BNT162b2 Vaccine: A 6-Month Follow-Up

Matusali

Sberna

Meschi

et al. 2022

Viruses

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To investigate the dynamic association among binding and functional antibodies in health-care-workers receiving two doses of BNT162b2 mRNA COVID-19-vaccine, SARS-CoV-2 anti-RBD IgG, anti-Trimeric-S IgG, and neutralizing antibodies (Nabs) were measured in serum samples collected at 2 weeks, 3 months, and 6 months from full vaccination. Despite the high correlation, results for anti-RBD and anti-Trimeric S IgG were numerically different even after recalculation to BAU/mL following WHO standards indications. Moreover, after a peak response at 2 weeks, anti-RBD IgG levels showed a 4.5 and 13 fold decrease at 3 and 6 months, respectively, while the anti-Trimeric S IgG presented a less pronounced decay of 2.8 and 4.7 fold. Further different dynamics were observed for Nabs titers, resulting comparable at 3 and 6 months from vaccination. We also demonstrated that at NAbs titers ≥40, the area under the receiver operating characteristic curve and the optimal cutoff point decreased with time from vaccination for both anti-RBD and anti-Trimeric S IgG. The mutating relation among the anti-RBD IgG, anti-Trimeric S IgG, and neutralizing antibodies are indicative of antibody maturation upon vaccination. The lack of standardized laboratory procedures is one factor interfering with the definition of a correlate of protection from COVID-19.

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WHO International Standard for evaluation of the antibody response to COVID-19 vaccines: call for urgent action by the scientific community

Cited by 131 publications

References 18 publications

Heterologous immunization with inactivated vaccine followed by mRNA booster elicits strong humoral and cellular immune responses against the SARS-CoV-2 Omicron variant

Heterologous immunization with inactivated vaccine followed by mRNA booster elicits strong humoral and cellular immune responses against the SARS-CoV-2 Omicron variant

Neutralizing Activity and SARS-CoV-2 Vaccine mRNA Persistence in Serum and Breastmilk After BNT162b2 Vaccination in Lactating Women

Differential Dynamics of SARS-CoV-2 Binding and Functional Antibodies upon BNT162b2 Vaccine: A 6-Month Follow-Up

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