Moderna : ESCMID 2026 (mRNA-1273 & mRNA-1283 Effectiveness and safety of variant updated Covid vaccines)

Published: 2026-04-22 08:32:08 ET MRNA

Published on 04/22/2026 at 08:32 am EDT

Effectiveness and Safety of Variant-Updated COVID-19 Vaccines

Spyros Chalkias,1,* Amparo L. Figueroa,1 Erick F. Mayer,1 Kimball Johnson,2 Robert Springer,3 Jarrett Lowe,1 Ann Cripple,1 Veronica Urdaneta,1 Wenqin Xu,1 Xin Cao,1 Jing Feng,1 Bethany Girard,1 Arshan Nasir,1 Rahnuma Wahid,1 Darin K. Edwards,1 David C. Montefiori,4 Rituparna Das1

1Moderna, Inc., Cambridge, MA, USA; 2CenExel, Decatur, GA, USA; 3DelRicht Research, Springer Wellness and Restorative Health, Atlanta, GA, USA;

4Duke University Medical Center, Durham, NC, USA

*Presenting author: Spyros Chalkias

SARS-CoV-2 continues to evolve antigenically, with ongoing emergence of new subvariants containing spike protein mutations associated with altered neutralisation sensitivity1

Periodic updates of COVID-19 vaccine formulations are implemented to maintain alignment with circulating SARS-CoV-2 strains2

mRNA-1273 and mRNA-1283 are lipid nanoparticle-encapsulated mRNA vaccines targeting the

SARS-CoV-2 spike protein. mRNA-1273 encodes the full-length prefusion stabilised spike protein, while mRNA-1283 encodes the receptor binding domain (RBD) and N-terminal domain (NTD) of the spike protein3-5

Updated 2025-2026 formulations of mRNA-1273.251 and mRNA-1283.251, which contain the SARS-CoV-2 LP.8.1 variant sequence, were evaluated in Phase 3b/4 open-label studies in individuals aged ≥65 years

and ≥12 to <65 years with underlying conditions associated with increased risk for severe COVID-19. Each study included an initial descriptive component (Part A) and a subsequent hypothesis-driven component (Part B) designed to further

characterise the immunogenicity and safety of the updated formulations

Here, we present interim immunogenicity and safety results from the descriptive components (Part A) of these Phase 3b/4 studies evaluating mRNA-1273.251 and mRNA-1283.251;

hypothesis-driven evaluations (Part B) are ongoing

To describe interim immunogenicity and safety following administration of updated mRNA-1273.251 and mRNA-1283.251 containing the LP.8.1 variant sequence in individuals at increased risk for severe COVID-19 (descriptive components)

To characterise cross-variant neutralising antibody (nAb) responses following administration of mRNA-1273.251 and mRNA-1283.251 against

contemporaneously circulating SARS-CoV-2 variants

Two independent Phase 3b/4 open-label studies (NCT06585241; NCT07089706) evaluated updated LP.8.1-containing mRNA-1273.251 and

mRNA-1283.251 formulations

Participants

Baseline demographics and clinical characteristics across study parts are presented in

Table 1

mRNA-1273.251

Part A (N = 103)

mRNA-1283.251

Part A (N = 172)

Age, years

Mean (SD)

61.5 (14.3)

56.3 (15.1)

Median (min, max)

64.0 (16.0, 94.0)

59.0 (15.0, 86.0)

Age group, n (%)

≥12 to <65 years

54 (52.4)

110 (64.0)

≥65 years

49 (47.6)

62 (36.0)

Sex, n (%)

Female

55 (53.4)

106 (61.6)

Male

48 (46.6)

66 (38.4)

Race group, n (%)

Asian

3 (2.9)

2 (1.2)

Black

57 (55.3)

64 (37.2)

Missing

2 (1.2)

Other

1 (1.0)

12 (7.0)

White

42 (40.8)

92 (53.5)

Ethnicity, n (%)

Hispanic or Latino

2 (1.9)

5 (2.9)

Not Hispanic or Latino

96 (93.2)

165 (95.9)

Baseline body mass index, n (%)

<30 kg/m2

48 (46.6)

76 (44.2)

≥30 kg/m2

55 (53.4)

96 (55.8)

Time since last prior COVID-19 vaccine, days

n 80

Mean (SD) 938.4 (452.7)

1045.1 (460.0)

Median (min, max) 913.0 (242.0, 1665.0)

1027.0 (199.0, 2031.0)

Table 1. Baseline Demographics of Study Participants (Safety Set)

Safety

mRNA-1273.251 and mRNA-1283.251 were well-tolerated through Day 29

No serious AEs, AEs of special interest, deaths, or AEs leading to study discontinuation were reported

Reported AEs were infrequent and considered unrelated to study vaccination

Immunogenicity

mRNA-1273.251 and mRNA-1283.251 elicited robust increases in nAb titres against the vaccine-matched LP.8.1 variant at Day 29 across age groups (Figure 1)

For mRNA-1273.251, geometric mean fold rise (GMFR) from baseline was 26.3

(95% CI: 15.6, 44.3) in participants aged ≥12 to <65 years and 15.4 (95% CI: 9.5, 25.0) in participants aged ≥65 years

For mRNA-1283.251, GMFR from baseline was 53.0 (95% CI: 36.7, 76.4) in participants aged ≥12 to <65 years and 36.7 (95% CI: 23.1, 58.4) in participants aged ≥65 years

Figure 1. Day 29 nAb Titres (ID50) Against LP.8.1 Following mRNA-1273.251 and mRNA-1283.251 (Part A, PPIS)

A. ≥12 to <65 years B. ≥65 years

Day 29 Cross-Neutralisation of Emerging Variants

Both mRNA-1273.251 and mRNA-1283.251 elicited substantial Day 29 increases in nAb titres against LP.8.1 and currently circulating variants (XFG, NB.1.8.1, and BA.3.2.2) (Figure 2)

Figure 2. nAb Responses Elicited by (A) mRNA-1273.251 and (B) mRNA-1283.251 Against Vaccine-Matched (LP.8.1) and Emerging Variants (XFG, NB.1.8.1, and BA.3.2.2), Fit-for-Purpose Analysis

LP.8.1

XFG

NB.1.8.1

BA.3.2.2

69.6 1973.3 47.9 952.4 109.8 2064.7 151.7 823.6

~28.3x

~19.9x

~18.8x

~5.8x

94.3 2252.1

58.2 1137.6

133.4 2182.8

163.6 825.9

~25.9x

~19.5x

~16.4x

~5.4x

51.4 1710.8

39.7 802.5

91.0 1956.9

140.6 821.4

~31.2x

~20.2x

~21.5x

~6.2x

Overall

10,000

1000

100

12-64 Years

nAb ID50 Titre

10,000

1000

100

≥65 Years

10,000

1000

100

Baseline Day 29 Baseline Day 29 Baseline Day 29 Baseline Day 29

LP.8.1

73.4 3827.2

58.8

XFG

2050.6

NB.1.8.1

BA.3.2.2

138.6

3818.4

159.9

1549.3

~47.9x

~35.2x

~27.5x

~9.2x

51.7 4226.6

41.6 1868.7

84.8 4090.7

132.4 1661.4

~73.9x

~46.4x

~48.2x

~11.8x

104.1 3478.3

82.1 2234.9

222.4 3573.3

193.0 1448.6

~31.5x

~27.2x

~16.1x

~7.2x

Overall

10,000

1000

100

Studies were conducted in individuals aged ≥65 years and ≥12 to <65 years who had ≥1 underlying condition associated with increased risk for severe COVID-19

Participants received a single dose of mRNA-1273.251 50 µg or mRNA-1283.251 10 µg

Immunogenicity assessments included

GMFR (95% CI) 26.3 (15.6, 44.3)

10,000

GMT, IU/mL (95% CI)

87.6 2300.9

1,000

1000

100

Day 1 Day 29

GMFR (95% CI) 15.4 (9.5, 25.0)

10,000

GMT, IU/mL (95% CI)

90.4 1394.6

1,000

1000

100

Day 1 Day 29

10,000

12-64 Years

nAb ID50 Titre

1000

100

C. ≥12 to <65 years D. ≥65 years

nAb responses at baseline and Day 29 against the vaccine-matched LP.8.1 variant

Exploratory analysis of Day 29 cross-neutralising antibody responses against currently circulating variants (XFG, NB.1.8.1, and BA.3.2.2) in a randomly selected subset of participants using a fit-for-purpose assay approach

Safety assessments included unsolicited adverse events (AEs; Days 1-29), serious AEs, AEs of special

1,000

10,000

62.0

3230.3

10,000

91.3

3433.9

1000

100

Day 1 Day 29 Day 1 Day 29

mRNA-1273.251 mRNA-1283.251

GMT, IU/mL (95% CI)

GMFR (95% CI) 53.0 (36.7, 76.4)

1,000

GMT, IU/mL (95% CI)

GMFR (95% CI) 36.7 (23.1, 58.4)

10,000

≥65 Years

1000

100

interest, and AEs leading to study withdrawal (through end of study)

GMFR, geometric mean fold rise; GMT, geometric mean titre; ID50, 50% inhibitory dose; nAb, neutralising antibody; PPIS, per-protocol immunogenicity set; RT-PCR, reverse transcription polymerase chain reaction.

The PPIS for the prespecified analysis comprised all enrolled participants who received either mRNA-1273.251 or mRNA-1283.251, had negative RT-PCR tests on Days 1 and 29, and had no major protocol deviations that could affect the integrity of key study data.

Neutralising antibody titres against LP.8.1 at Days 1 and 29 are presented for the following age groups: Panel A shows participants aged ≥12 and <65 years who received mRNA-1273.251; Panel B shows participants aged ≥65 years who received mRNA-1273.251. Panel C shows participants aged ≥12 and <65 years who received mRNA-1283.251. Panel D shows participants aged ≥65 years who received mRNA-1283.251. Antibody values reported as below the lower limit of quantification (LLOQ) are replaced by 0.5 × LLOQ. Antibody values greater than the upper limit of quantification (ULOQ) are replaced by the ULOQ.

Baseline Day 29 Baseline Day 29 Baseline Day 29 Baseline Day 29

ID50, 50% inhibitory dose; LLOQ, lower limit of quantification; LOD, limit of detection; nAb, neutralising antibody; ULOQ, upper limit of quantification. Dashed lines represent LOD. n ranges from 25-56 participants.

A fit-for-purpose approach was applied to enable rapid assay development and sample testing for newly emerging variants. Accordingly, LOD was applied for analyses across all 4 variants, although the LP.8.1 assay was fully validated and its LLOQ and ULOQ were established through a formal validation process. Antibody values below the LOD were imputed as 0.5 × LOD. Values above the ULOQ were not capped.

Updated LP.8.1-containing mRNA-1273.251 and mRNA-1283.251 elicited robust nAb responses against the vaccine-matched variant across age groups

Both mRNA-1273.251 and mRNA-1283.251 were well-tolerated through Day 29, with no reported serious AEs, AEs of special interest, or AEs leading to study discontinuation

Exploratory analyses demonstrated that both mRNA-1273.251 and mRNA-1283.251 elicited cross-neutralising antibody responses against currently circulating variants, including XFG, NB.1.8.1, and BA.3.2.2, but these were lower than the LP.8.1 responses

These findings support the use of updated variant-containing mRNA vaccines to maintain nAb responses against evolving SARS-CoV-2 variants

References

Chen L, et al. Lancet Infect Dis. 2025;25(4):e193.

US Food and Drug Administration. COVID-19 Vaccines (2025-2026 Formula) for Use in the United States Beginning in Fall 2025. May 22, 2025. https://www.fda.gov/vaccines-blood-biologics/industry-biologics/covid-19-vaccines-2025-2026-formula-use-united-states-beginning-fall-2025

Jackson LA, et al. N Engl J Med. 2020;383(20):1920-1931.

Chalkias S, et al. Lancet Infect Dis. 2025;25(11):1230-1242.

Chalkias S, et al. J Infect Dis. 2025;231(4):e754-e763.

Acknowledgments

Medical writing and editorial assistance were provided by Nicole Prodan, PhD, of MEDiSTRAVA in accordance with Good Publication Practice (GPP 2022) guidelines, funded by Moderna, Inc., and under the direction of the authors.

This study was funded by Moderna, Inc.

Disclosures

SC, ALF, EFM, JL, AC, VU, WX, XC, JF, BG, AN, RW, DKE, and RD are employees of Moderna, Inc., and may hold stock/stock options in the company. KJ is an employee of CenExel and holds stock in the company. DCM reports laboratory funding from Moderna, Inc. RS has nothing to declare.

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Moderna Inc. published this content on April 22, 2026, and is solely responsible for the information contained herein. Distributed via Public Technologies (PUBT), unedited and unaltered, on April 22, 2026 at 12:31 UTC.