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A Study of Measles antibody levels from birth till 9 months of age:
Correlation with maternal titres and Maternal nutrition
RR JOSHI*, PS GAMBHIR**

Objective : To correlate measles IgG levels in mothers and their new born babies, study pattern of decline of these antibodies till 9 months and correlate them with maternal nutritional parameters.

Design : Prospective.
Methods : Blood of 23 full term babies and their mothers was taken at birth. Then blood from these babies was withdrawn at 11/2, 21/2, 31/2 and 9 months of age. Measles IgG levels was estimated by ELISA. Mother’s body mass index was calculated and haemoglobin and serum proteins were done.

Results : All mother were seropositive for measles IgG while 87% newborns were seropositive. Seropositivity increased from 87% at birth to 95.65% at 11/2 months, then decreased to 69.57% and 65.22% at 21/2 months at 31/2 respectively and then there was a sharp decline to 17.39% at 9 months of age.

Conclusion : Measles antibody levels in cord sera and maternal sera showed a high degree of correlation. Mother’s nutritional status had no influence on maternal titres and cord titres. From 31/2 to 9 months of age there is loss of protective level of antibodies with almost complete loss of majority at 9 months. Measles vaccination strategy may be modified to 4-6 months rather than at 9 months. Validity of this suggestion should be ascertained by undertaking further studies.

INTRODUCTION

Measles remains a major cause of childhood morbidity and mortality in developing countries. Control of measles in
developing countries is complicated by pattern of measles transmission in which children are infected soon after they lose their protection from passive maternal antibodies against measles between 5 and 11 months of age. There is no single ideal
age for measles vaccination in all countries, since 3 important determinants vary between infant population which are : a) age specific incidence of measles, b) age specific prevalence of maternal measles antibody, c) age specific serocnversion rate
following vaccination.

1 Though there are many studies on the seroepidemiology of measles in our country, there are very few which analyse these aspects of the measles problem in infants less than 9 months of age, especially when there is rapid waning of passively
acquired immunity.

There are almost no studies showing correlation between maternal nutrition and the passive immunity acquired by the baby. Therefore the aim of this study was also to correlate the maternal nutrition and passive immunity (i.e. the baby titres) so that the maternally acquired protection can be improved. The acquisition of passive immunity and its evolution till active immunization was found out.

METHODS
The study population included 23 mother-infant pairs selected from the labour ward of a large teaching institute.

Twenty three full-term delivered babies and their mothers were taken for study. 2 ml blood by venepuncture of mother and cordblood of her newborn was taken. Then 2 ml blood of same 23 babies was withdrawn at 11/2, 21/2, 31/2 and 9 months of their age. Blood was collected in plain autoclaved bulbs. Serum was separated and IgG levels for measles antibodies was estimated by ELISA which is one of the most widely accepted methods worldwide and has got sensitivity, specificity and reproducibility comparable to other serological tests like haemagglutination inhibition (HI), immunofluorescence and complement fixation.

Mother’s body mass index (BMI in kg/m2) was calculated. Also haemoglobin (Sahil’s method) and serum proteins was done on mother’s blood sample.

Infants with a history of measles or with fever, rash and conjunctivitis suggestive of viral exanthem were excluded. Infants with recent history of measles in household or neighbourhood were also excluded from the study. Serum from collected blood samples was separated and stored at -20° C.

Procedure of ELISA (enzyme linked immunosorbent assay) Test sera, calibrator, positive and negative control sera were diluted 1:21 in serum diluent and 100 µL added to the wells. Serum diluent was added to the reagent blank well. They were incubated at room temperature for 20 min. Then wash procedure was performed twice and liquid was blotted out from the wells. 100 µL conjugate was added to each well and incubated at room temperature for 20 min. Wash procedure was repeated. Then 100 µL substrate/chromogen solution was added to each well and incubated at room temperature for 10 min. Reaction was stopped by adding 100 µL L 1N
H2SO4. After 5 minutes, developed colour was red on ELISA plate reader equipped with 450 nm filter. Mean absorbance of the calibrators was multiplied by the factor assigned. This is the calibrator value. ISR (Immune status ratio) value for each patient sample
was calculated by dividing the sample absorbance by the calibrator value.

ISR Vlalue
Result
   
< 0.9 Negative. No detectable antibody to
measles by ELISA.
   
0.91-1.09 Equivocal. Samples should be retested.
   
= 1.1 Positive. Indicates presence of detectable
antibody to measles by ELISA.

 

OBSERVATIONS AND RESULTS
There is a very high degree of correlation between measles antibody levels in cord sera and corresponding maternal sera. (t-test applied, r=0.77, p < 0.001) (Tables 1, 2, 3, 4, 5).

DISCUSSION
Prevalence of seropositivity and seronegativity in the present study

Analysis of 23 pairs of maternal and cord sera

TABLE 1
Distribution of measles antibody levels in infants
Age in comp-
leted months
No. of infants
studied
Elisa antibody titres (ISR values)Geometric
_______________________________________
< 0.9 0.9-1.09 = 1.1
Seropositives alone
mean titres
No.

%

Birth 23
3 0 20
     
2.299 20 86.96
11/2 months 23
1 0 22
1.970 22 95.65
21/2 months 23
7 0 16
1.446 16 69.57
31/2 months 23
8 0 16
1.029 15 65.22
9 months 23
19 0 4
0.609 4 17.39


Geometric mean titre decreases from 2.299 at birth to 1.029 at 31/2 months and then sharply to 0.609 at 9 months. Seropositivity decreases from 86.96% at birth to 17.39% at nine months. There is increase in seropositivity to 95.65% at 11/2 months from birth

TABLE 2
Influence of body mass index on seropositivity in mothers

BMI of Mothers Maternal titres
Maternal titres
31.04
2.63
19.22
5.13
21.36
4.13
17.19
2.90
18.67
2.15
18.42
3.00
18.37
3.05
16.80
3.10
17.29
2.30
16.44
6.25
16.45
3.01
16.65
3.29
15.09
4.16
17.31
2.40
17.12
5.91
16.87
7.38
17.78
7.00
23.51
2.32
22.21
1.50
19.92
2.95
19.90
2.96
20.70
2.06
20.72
2.07

Correlation coefficient between BMI of mothers and maternal titres was calculated, r = -0.36, t = 1.77, p > 0.05; Though there seems correlation, it is not statistically significant

samples, for measles antibody levels showed that all the mothers were strongly seropositive (100%). Of the 23 cord sera studied 13% (3/23) were seronegative and 87% (20/23) were seropositive. 34.78% pairs showed identical concentration of measles antibody in mother and baby. Mehta et al recorded 70% seropositivity in mothers and 62% in infants by HI method,2 whereas Kenyan Govt., WHO study observed 100% serepositivity in all the maternal and cord sera by HI method.


Influence of mother’s nutrition on antibody




TABLE 3
Influence of maternal haemoglobin on seropositivity in
mothers

Acceptable haemoglobin is = 12 gm%
Low haemoglobin is < 12 gm%


Hb of mother Measles Ab in mother Total
  +ve -ve  
Acceptable haemoglobin 16 0 16
Low haemoglobin 7 0 7
Total 23 0 23

R = -0.33, t = 1.6, p > 0.05
Haemoglobin of mother is negatively correlated with maternal antibody titres, however this correlation is not statistically
significant

TABLE 4
Influence of maternal serum proteins on seropositivity in
mothers

Acceptable serum proteins is = 6.5 gm%
Less than acceptable serum proteins is < 6.5 gm%

Serum proteins of mother Measles Ab in mother   Total
  +ve -ve  
Acceptable serum proteins 19 0 19
Less than acceptable serum proteins 4 0 4
Total 23 0 23

r = -0.07, t = 0.3, p > 0.05
Maternal serum proteins has got no statistically significant influence on meternal titres

 

TABLE 5

Correlation coefficient(r) of cord titres with mother’s
parameters

Mother’s parameters ‘r’ of cord titres


Haemoglobin -0.11
Serum proteins -0.13
BMI -0.28

Maternal haemoglobin, serum proteins and BMI have no
statistically significant influence on cord titres


titres
Maternal haemoglobin, serum proteins and BMI
did not show correlation with the maternal titres and cord titres and hence the evolution of these titres.

Halsey

in a study on Haitian infants, had speculated that Haitian mothers with lower titres
might have been undernourished at some time in their lives. However, they found no correlation between maternal weight, height or percentage of ideal weight or height and haemagglutination inihibition antibody titres in the mothers or seroconversion rates in their
infants.

Evolution of passive maternal antibodies in infants till 9 months of age

Analysis revealed that seropositivity increased from 87% at birth to 95.65% at 11/2 months. Only two samples showed this increase in seropositivity, however according to the ELISA kit manufacturer’s manual the titre level difference was < 30% and therefore insignificant.

The age at which maximum loss of protective levels of maternal measles antibodies occurs in infants has been exclusively studied by many authors abroad and in India. Khare et al observed that significant decline in protective levels of antibodies occurred by 7 months of age. Seropositivity observed declined from 100% at one months to 50% at 4-5 months and then to 10% at 7 months.4 Dabies et al observed that the proportion of detectable measles antibodies dropped from 95.8% at 2 months to 48.5% at 4 months of age and to 8.2% by 7 months.5 Rogers et al from New Guinean found that by 6 months of age no child had detectable antibodies

Analysis of seropositivities in different age groups revealed that at birth, 11/2, 21/2 and 31/2 months, that the proportion of seropositive infants is higher than at 9 months age group. Further analysis of GMT titres of all samples and seropositives alone revealed that GMT of seropositives alone at birth, 11/2 and 21/2 months was significantly higher than that at 31/2 months and still less at 9 months age group. This implied that there is not much loss of maternal antibodies at 11/2, 21/2 months of age and a gradual decline from birth to 31/2 months.


Comparison of measles antibody levels at 31/2 (65.22%) and at 9 months (17.39%) showed a significant loss of antibodies at 9 months. These infants became seronegative irrespective of their maternal titres. The rest of infants who were seropositive (4/23) i.e. 17.39% had shown a decline of titres till 31/2 months and then sudden increase (2 or 3 fold) at 9 months age. This confirms that these high levels of measles antibodies have been acquired consequent to measles infection. Since none of them gave a history suggestive of clinical illness akin to measles, this serological evidence of infection is probably due to subclinical or unrecognised infection which is a documented phenomenon by authors.3,7 Based on the available data, we can derive inferences regarding the susceptibility at different ages. Among the neonates studied 13% were seronegative and hence were susceptible to measles infection even at birth. However, their mothers were seropositive but in less titres than that of other mothers. At 11/2 months of age only 4% infants were seronegative. These mothers showed less titres than other mothers. However, this decline of seronegativity may be due to subclinical infection. At 21/2 months of age 30.43% and at 31/2 months 34.78% infants were seronegative and thus susceptible to infection. At 9 months 82.61% were seronegative, consequent to loss of maternal measles antibody, thus they remain potential targets for measles infection. It is relevant to note that all these were infants of seropositive mothers. Among the remaining infants 4/23 who were seropositive in high titres at 9 months were probably exposed already to a subclinical infection.

These findings help us to conclude that the relevance of maternal antibody levels as a determinant of susceptibility ceases by 31/2 months of age. Maternal antibody levels are also not predictive of whether an infant is going to be seronegative or would acquire subclinical infection.

It is a well known fact that mortality due to measles is highest among the young infants. Available data from this study indicates that the infants show susceptibility to measles from 31/2 months onwards, by means of seronegativity or seropositivity - suggestive of previous subclinical infection. These facts lead us to the conclusion that 31/2 to 9 months age period is a susceptibility age for measles in our population. Thus the problem of persisting maternal antibodies interfering with effective serocoversion
following vaccination does not arise between 31/2 and 9 months of age. Moreover, with the availability of vaccine (Edmonston-Zagreb) which produces better seroconversion at younger age, adequate vaccine coverage becomes much easier.8,9

Thus we can conclude that our vaccination strategy has to be modified from 9 months to 4-6 months of age. In future most of the babies would be acquiring passive immunity from mothers who are vaccinated and therefore not naturally infected. This protective immunity titres acquired from a vaccinated mother would be much less and would also wane quickly than the passive immunity transferred from naturally infected mothers.10 Hence in future we should anticipate bigger epidemics of measles due to this poor passive protection, and act accordingly. The best strategy would be to vaccinate at 4-6 months of age and revaccinate later on between 12-15 months age or at school going age to increase the immunity against measles. The validity of this suggestion could be further ascertained by undertaking relevant studies.

ACKNOWLEDGEMENT
We are grateful to Januka Trust for their help during the study.


REFERENCES

1. Measles immunity in the first year after birth and the optimum age for vaccination in Kenyan Chidren. Collaborative study
by the Ministry of Health of Kenya and the World Health Organization. Bull World Health Organ 1977; 55(1) : 21-

2. Mehta NA, Nanawati AND, Jhala HI, Sant MV. Seroepidemiology of measles in Bombay. Indian J Med Res 1972; 60 : 661-9.

3. Halsey NA, Boulos R, Mode F, et al. Responses to measles vaccine in Haitian infants 6 to 12 month old. Influence of
maternal antibodies, malnutrition and concurrent illnesses. N Engl J Med 1985; 313(9) : 544-9.

4. Khare S, Dutta A, Kumari S, Basu RN. Seroepidemiology of measles in Delhi: implications for age of vaccination. Indian
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5. Dabis F, Sow A, Waldman RJ, et al. The epidemiology of measles in a partially vaccinated population in an African city
: Implications for immunization programs. Am J Epidemiol 1988; 127(1) : 171-8.

6. Rogers S, Sanders RC, Alpers MP. Immunogenicity of standard dose Edmonston-Zagreb measles vaccine in highland Papua New Guinean children from four months of age. J Trop Med Hyg 1991; 94(2) : 88-91.

7. John TJ, Joseph A, George TI. Epidemiology and prevention of measles in rural South India. Indian J Med Res 1980; 72 : 153-8.

8. Tidjani O, Grunitsky B, Guerin N, et al. Serological effect of Edmonston-Zagreb, Schwarz and AIK-C measles vaccine strains given at ages 4-5 or 8-10 months. Lancet 1989(2) : 1357-60.

9. Shaikh N, Raut SK, Bedekar SS, Phadke MA, Banerjee K. Experience with a measles vaccine manufactured in India.
Indian Pediatr 1992; 29 : 883-7.

10. Maldonado YA, Lawrence EC, Dehovitz R, Hartzeu H, Albrecht P. Early loss of passive measles antibody in infants
of mothers with vaccine induced immunity. Pediatrics 1995; 96(3) : 447-50.



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