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Impact of withholding breastfeeding around the time of Rotarix® vaccination

on the immunogenicity of Rotarix® vaccine

A Randomized Trial

S. Asad Ali, MD, MPHDepartment of Pediatrics and Child Health

Aga Khan UniversityPakistan

1

Why is the immunogenicity of rotavirus vaccines lower in low income settings?

2


• Environmental Enteropathy

• Higher anti-RV antibodies in mother’s blood with transplacental transmission

• Higher anti-RV antibody levels in breast milk

• Concomitant OPV administration

• Coexistent intestinal infections3

5

FIGURE 1.

Cumulative frequency profiles of rotavirus-specific antibodies in breast milk specimens

from mothers in India, Vietnam, Korea and the United States. Milk specimens were tested

for IgA (A) and neutralizing activity against vaccine strains Rotarix (B), RotaTeq G1 (C),

and 116E (D) as described in the text. Nearly all Indian women had an IgA titier >16 versus

all other women. The median IgA and neutralizing titers and the distribution of titers for

breast milk from Indian women were higher than all others. The values of significance

between Indian women and those from Korea, Vietnam, and the United States are indicated.

NA indicates neutralizing antibody.

Moon et al. Page 8

Pediatr Infect Dis J . Author manuscript; available in PMC 2013 July 08.

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Moon SS et al. Inhibitory effect of breast milk on infectivity of live oral rotavirus vaccines. Pediatr Infect Dis J. 2010

Primary Objective

To compare the immunogenicity of Rotarix® in infants

whose breastfeeding was withheld one hour before

through one hour after vaccination with each Rotarix®

dose to that in infants who were breastfed at the time of

vaccination

7

Secondary Objective

To determine the effect of rotavirus neutralizing activity inbreast milk on the immunogenicity of Rotarix® vaccine ininfants

8

Trialprofile

RV=RotarixVaccine

B=BloodDraw

Randomiza on

1:1

RV/B B

10weeks6weeks 14weeks 18weeks

(n=210)

(n=210)

RV RV/B

Birth

Breas eedingimmediatelybeforeRVadministra on

Breas eedingwithheldforonehourbeforeanda erRVadministra on

RV/B BRV RV/B

(n=200)

(n=200)

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Randomized (400)

Breastfeed Withholding group(200)

IgA≥20 U/mL (3)

Non-compliance with blood draw (1)

Lost to follow up/Dropout

Refusal (9)

Illness (1)

Moved from Study Area (5)

Per Protocol (181)

Immediate Breastfeeding group(200)

IgA≥20 U/mL (6)

Non-compliance with blood draw (1)

Non-compliance with breastfeeding schedule (5)

Lost to follow up/Dropout

Refusal (9)

Death (1)

Moved from Study Area (6)

Per Protocol (172)

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Withholding Arm(N = 200)

Immediate Breastfeed Arm(N = 200)

Male 45 % 54 %

Age in Weeks 6.3 (0.5) 6.3 (0.5)

Weight (g) at 6 weeks 3939.1 (619.2) 4047.5 (594.7)

Age of visit in weeks†

Visit 2 10.4 (0.5) 10.4 (0.6)Visit 3 14.6 (0.6) 14.6 (0.6)Visit 4 18.7 (0.7) 18.7 (0.7)

†per-protocol population

Baseline Characteristics and Age at visits

Age at sample (weeks)

Withholding ArmImmediate

Breastfeed Arm

P-Value(N=181) (N=172)

Seroconversion

rate95 % CI

Seroconversion

rate95 % CI

14 (after 2 doses)

16.6% (11.8; 22.6) 29.1% (22.8; 36.2) 0.005

18 (after 3 doses)

28.2% (22.1; 35.1) 37.8% (30.8; 45.2) 0.070

Anti-rotavirus IgA antibody seroconversion rates in the per protocol population

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Anti-rotavirus IgA geometric mean titers (GMT) for seroconverted subjects after 2 or 3 doses

Age at Sample(weeks)

Withholding Arm Immediate Breastfeed Arm

n GMT 95 % CI n GMT 95 % CI P value

14 (after 2 doses)a 30 194.4 (126.2;299.3) 50 104.4 (77.3; 140.9) 0.016

18 (after 3 doses) b 51 125.4 (91.0; 172.9) 65 91.8 (69.1; 121.8) 0.147

aIncludes only anti-rotavirus IgA seropositive subjects at 14 weeksbIncludes only anti-rotavirus IgA seropositive subjects at 18 weeks

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14 (after 2 doses)a 30 194.4 (126.2;299.3) 50 104.4 (77.3; 140.9) 0.016

18 (after 3 doses) b 51 125.4 (91.0; 172.9) 65 91.8 (69.1; 121.8) 0.147


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14 (after 2 doses)a 30 194.4 (126.2;299.3) 50 104.4 (77.3; 140.9) 0.016

18 (after 3 doses) b 51 125.4 (91.0; 172.9) 65 91.8 (69.1; 121.8) 0.147


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Association of Maternally Derived Neutralizing Antibody (MDNA)* titers at 6 weeks with rotavirus seroconversion at

14 weeks (post 2 doses)

MDNA at 6 weeks(Percentile)

Withholding Arm Immediate Breastfeed Arm Combined

(N= 93) (N= 85) (N= 169)

Seroconversion rate Seroconversion rate Seroconversion rate

< 25 22.5% 38.8% 31.4%

> 75 5.7% 22.2% 12.4%

P= 0.026 P= 0.157 P =0.003

*MDNA measured using 89:12 strain, which is precursor to Rotarix vaccine

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(N= 93) (N= 85) (N= 169)


< 25 22.5% 38.8% 31.4%

> 75 5.7% 22.2% 12.4%

P= 0.026 P= 0.157 P =0.003


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(N= 93) (N= 85) (N= 169)


< 25 22.5% 38.8% 31.4%

> 75 5.7% 22.2% 12.4%

P= 0.026 P= 0.157 P =0.003


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14 or 18 weeks (post 3 doses)



(N= 93) (N= 85) (N= 169)


< 25 37.5% 46.9% 42.7%

> 75 11.3% 19.5% 14.6%

P= 0.005 P= 0.012 P <0.0001


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(N= 93) (N= 85) (N= 169)


< 25 37.5% 46.9% 42.7%

> 75 11.3% 19.5% 14.6%

P= 0.005 P= 0.012 P <0.0001


25





(N= 93) (N= 85) (N= 169)


< 25 37.5% 46.9% 42.7%

> 75 11.3% 19.5% 14.6%

P= 0.005 P= 0.012 P <0.0001


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Low BMNA in Breast

Milk at 10 weeks

High BMNA in Breast

Milk at 10 weeks

Difference in

seroconversion P-value

(<50 %ile) (>50 %ile)

Time pointMDNA at 6

weeks Seroconversion rate Seroconversion rate

14 weeks (post 2

doses)

<50 %ile 44.4% 20% 24.4% 0.019

>50 %ile 29% 27.3% 1.8% 1

18 weeks (post 3

doses)

<50 %ile 38.9% 38% 0.9% 1

>50 %ile 45.2% 32.7% 12.4% 0.353

Serum Anti-Rotavirus IgA Seroconversion in Immediate Breastfeeding Group, by MDNA and 10-Week BMNA Level

MDNA Maternally derived neutralizing antibodies; BMNA Breast milk neutralizing activity

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Low BMNA in Breast

Milk at 10 weeks

High BMNA in Breast

Milk at 10 weeks

Difference in


(<50 %ile) (>50 %ile)

Time pointMDNA at 6


14 weeks (post 2

doses)

<50 %ile 44.4% 20% 24.4% 0.019

>50 %ile 29% 27.3% 1.8% 1

18 weeks (post 3

doses)

<50 %ile 38.9% 38% 0.9% 1

>50 %ile 45.2% 32.7% 12.4% 0.353



28

Low BMNA in Breast

Milk at 10 weeks

High BMNA in Breast

Milk at 10 weeks

Difference in


(<50 %ile) (>50 %ile)

Time pointMDNA at 6


14 weeks (post 2

doses)

<50 %ile 44.4% 20% 24.4% 0.019

>50 %ile 29% 27.3% 1.8% 1

18 weeks (post 3

doses)

<50 %ile 38.9% 38% 0.9% 1

>50 %ile 45.2% 32.7% 12.4% 0.353



Summary of Findings

• Withholding breast feeding around the time of RV1 vaccine administration did not lead to increased anti-rotavirus IgA seroconversion.

• To our surprise, IgA seroconversion after two RV1 doses at 6 and 10 weeks was significantly greater in immediately breastfed infants compared with those in whom breast milk was withheld!

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Some nuances!

• GMT in seropositive infants at 14 weeks was higher in the withholding arm compared to the immediate arm

• Lower seroconversion in infants in the immediate feeding arm with low MDNA/higher BMNA after two doses suggests that ingesting breast milk with higher BMNA at the same time as vaccine may reduce the immune response in some infants

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Summary

• Although serum rotavirus IgA is not a perfect correlate of protection, our findings suggest that substantially improved clinical protection is not likely with the strategy of withholding breastfeed around the time of vaccination.

• We suggest breastfeeding can continue ad lib around the time of RV1 administration.

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But why was serum rotavirus IgA seroconversionhigher in the immediate breastfeed group?

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• Chance finding?

• Additional buffering of gastric acid at the time of vaccine administration?

• Something immunogenic in breast milk ??

Study Team:• Aga Khan University

Asad Ali (PI)

Momin Kazi

Anita Zaidi

Rota study team

Patients and their families

Margaret Cortese

Umesh Parashar

Baoming Jia

SungSil Moon

Jessica Fleming

Chris Victor

Kathy Neuzil

Duncan Steele

CDC

Monica McNeal

University of Cincinnati

PATH

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