Influenza Clinical Trial
Official title:
Effect of Maternal Vitamin A Supplementation on Maternal Immune Response to Inactivated Influenza Vaccination, and on Passive Protection of Infants
Influenza viral infection can cause serious illness among young infants 0-6 months of age.
However, inactivated influenza vaccine is not recommended for this age group but pregnant
women can be vaccinated during 2nd - 3rd trimester to induce passive immunization of their
infants. Nevertheless vitamin A deficiency is highly prevalent among pregnant women in
Bangladesh, >50% pregnant women consume less vitamin A than the recommended level. Given the
fact that both clinical and sub-clinical vitamin A deficiency impair vaccine specific
immunity, in this proposed study, we aim to investigate whether maternal vitamin A
supplementation improve influenza vaccine specific immune responses among pregnant women and
the passive protection of their infants.
In a placebo controlled clinical trial, sixty six mothers will be randomly assigned to
receive either 10,000 IU vitamin A or placebo capsules weekly from second trimester to 6
month postnatal period. At 26-28 weeks of gestation, all mothers will be vaccinated with
inactivated, trivalent influenza virus vaccine. Maternal and cord blood will be collected
for vitamin A and influenza virus specific IgG assessment. Colostrum and breast milk at
6-month will be collected for vitamin A and influenza virus specific secretory IgA
assessment. Venous blood (2-3 ml) will be obtained from all infants at the age of 6 months
for vitamin A and influenza virus specific IgG assessment as well as infants' nasal swab for
influenza virus specific secretory IgA.
Influenza morbidity affects the entire population and has an enormous impact upon the
economic burden and the health care system, particularly causing serious illness among young
infants 0-6 months of age. Recent studies show high rates of influenza illness and
hospitalization among infants at this age group in industrialized countries (Chiu et al.,
2002; Poehling et al., 2006) and influenza related childhood mortality is highest in young
infants before 6 months of age (Bhat et al., 2005). Unfortunately, inactivated influenza
vaccine is not recommended for this age group, but pregnant women can be vaccinated during
2nd - 3rd trimester. Thus the strategy of passive immunization (from mother) of infants is
the effective way to combat this infection among young infants. This approach adopted in US
since 1997 and recommended by WHO since 2005.
Upper respiratory tract is the portal of virus entry and primary site of replication (Gluck
et al., 1994; Muszkat et al., 2000). Thus the importance of the presence of effective
mucosal antibodies at the entry site of virus is essential to neutralize the virus and
prevent infection (Meitin et al., 1994). Secretory IgA (sIgA) is the primary mucosal
antibody, accounting for ~70% of the body's total antibody production (Brandtzaeg, 1994).
sIgA has been shown to mediate nasal anti-influenza mucosal immunity (Renegar & Small, 1991)
and therefore indicates the importance of vaccination strategies that trigger specific
antibody production at mucosal surfaces as well as the importance of dietary nutrients to
trigger the release of mucosal neuropeptides necessary for maintenance of the mucosal immune
system (Renegar et al., 2001). A number of clinical trials examined the effect of vitamin A
supplementation in humans on indicators of mucosal immunity. Supplementation to human
immunodeficiency virus infected pregnant women is associated with improved gut permeability
in their infants at 14 weeks as measured by lactulose/mannitol (L/M) urinary excretion test
(Filteau et al., 1999). While vitamin A supplementation during pregnancy (Semba et al.,
1999) or the early postpartum period (Filteau et al., 2001) show no effect on total sIgA in
breast milk, rather vitamin A in milk has been shown to inhibit the growth of both enveloped
and non-enveloped viruses (Clarke & May, 2000). However, total sIgA level of vitamin
A-sufficient children has been detected significantly higher than that of vitamin
A-deficient children (Lin et al., 2007). In animal model, vitamin A supplementation
increases both total and antigen specific sIgA-containing cells in the mucosa, which in turn
improves the survival rate (Nikawa et al., 2001) During early infancy breast milk is the
predominant source of vitamin A and to date no study investigates the effect of prenatal
vitamin A supplementation and vaccination on the vaccine specific mucosal sIgA responses in
offspring. Although maternal IgA is not transplacentally transferred to the infants, but
increased vitamin A and vaccine specific sIgA in breast milk as a result of maternal vitamin
A supplementation may enhance infant's nasal sIgA responses that in turn may provide
improved passive protection among young infants.
In our recent study (Mother'SGift Project, funded by Thrasher Research Fund), we have
detected that maternal influenza vaccination can reduce influenza illness substantially in
young infants up to 6 months of age in Bangladesh (Zaman et al., 2008). On the other hand
the prevalence of vitamin A deficiency among pregnant women in Bangladesh as well as in
other developing countries is very high. More than half of the pregnant women in Bangladesh
consume less vitamin A than the recommended dietary allowance and have low vitamin A status
(serum retinol <1•05 μmol/L) with approximately one-fifth of them classified as deficient
(serum retinol <0•70 μmol/L) (Ahmed et al., 2003; Lee et al., 2008). Nonetheless, there is
conclusive scientific evidence suggesting several aspects of both innate and adaptive
immunity are compromised by clinical and subclinical vitamin A deficiency (Stephensen,
2001). In another study, we observed a significant positive association between primary
yellow fever viral vaccine specific lymphocyte blastogenesis / antibody responses and body
vitamin A store (Ahmad et al., 2008). Thus in view of the potential immune regulatory roles
of vitamin A, it is of interest to investigate whether maternal vitamin A supplementation
along with influenza vaccination could be used as public health intervention strategy to
combat both influenza infection and vitamin A deficiency simultaneously among mothers and
young infants in developing countries.
Research Design and Methods:
Study Site: This study will be carried out at ICDDR,B; Dhaka, Bangladesh. Three urban
maternity clinics located at Mirpur area of Dhaka city will be selected for approaching
mothers who visit the clinic in the first trimester and who are the residence of the nearby
community.
Study Subject: The inclusion criterion is to enroll mothers at the beginning of second
trimester (i.e. approximately 12 weeks of gestation), willing to stay in Dhaka during
pregnancy and willing to admit in the clinic at delivery. The gestational age will be
determined by self-reported LMP, which is likely be underestimated in most cases. A two-week
variation will be acceptable in this proposed study. The exclusion criteria are: history of
systemic disease, previous complicated pregnancies or of pre-term delivery, abortion,
congenital anomaly, and hypersensitivity to influenza vaccine or receipt of the vaccine.
Overview of Experimental Design: This is a placebo-controlled, double-masked and randomized
trial. The overall study design is outlined in Figure 1, timeline and hypothetical duration
of the proposed protocol related activities are illustrated in Table 1. To allow scheduling
of the sample collection, storage and assay with the number of hired field attendants and
lab facilities that will be available, we plan to enter approximately five pregnant mothers
per week into this study in the first three-month period of the study (Table 1). Informed
written consent will be obtained from the mothers. Sixty-six pregnant women will be
randomized to receive either weekly 10,000 IU vitamin A or placebo (corn oil) capsules and
blood will be collected for serum vitamin A assessment. Randomization will be stratified by
three clinics using balanced block design. This weekly supplementation will continue until 6
months postpartum. The supplementing vitamin A dose to be used in this study is similar to
the doses used weekly among pregnant women in other studies (Semba et al., 1999; Cox et al.,
2006) and shown to be safe. Field workers will deliver the supplements to mothers, in person
and will directly observe their consumption. At 26-28 weeks of gestation, all mothers will
receive inactivated, trivalent influenza virus vaccine (GlaxoSmithKline; Dresden, Germany).
Standard inactivated trivalent influenza A/H3N2, A/H1N1, and B strains as recommended by WHO
for the Northern Hemisphere will be obtained from commercial sources for this project. Study
physician will administer the vaccine intramuscularly. At delivery, cord blood and colostrum
will be collected for Influenza specific IgG and sIgA assessment respectively as well as
vitamin A concentration. Birth weight and length of the newborn babies will also be
recorded. At 6-month, breast milk will be collected for vitamin A and influenza virus
specific sIgA assessment and venous blood (2-3 ml) from infants (6 mo of age) will be
obtained for vitamin A and influenza virus specific IgG assessment as well as infants' nasal
washings for influenza virus specific sIgA assessment. Our proposed study will not hamper
the existing prenatal care for the mothers such as folate/iron supplementation or existing
infant vaccination program in Bangladesh.
Randomization: Each mother will be given a unique randomly generated identification number,
which will indicate the study group she is assigned to. The same ID will be labeled on the
bottle containing 60 capsules. Field attendants will use these capsules for weekly
supplementation ensuring the ID no of the mother and bottle ID are same. A third party (ACME
laboratories, Dhaka Bangladesh) will prepare and supply vitamin A or placebo capsule in
bottles, labeled with ID numbers from a list of numbers. The responsible personnel will keep
it confidential until the end of study
Sample collection: Peripheral blood from mother, cord blood, colostrum, breast milk,
peripheral blood and nasal washings from infants will be collected as described in Figure 1.
Nasal secretions will be obtained by introducing wicks (cotton applicators) into the nostril
and gently rotating for 90s as described previously (Wright et al., 1996). The wicks will be
extracted into 1mL PBS, centrifuged, and the supernatants will be collected. All samples
will be frozen until tested simultaneously.
Serological evaluation: We have chosen to investigate the humoral immune responses only to
one influenza antigen because the purpose of this proposed study is to evaluate the effect
of maternal vitamin A supplementation on the infants' passive antibody levels, thus it is
prudent to investigate immune responses to one antigen. The following parameters of vitamin
A and Influenza A specific humoral immunity will be tested.
Vitamin A assessment: Vitamin A content in plasma, serum, colostrum and breast milk will be
measured by standard HPLC method in place in the Nutritional Biochemistry Lab of LSD.
Hemagglutination inhibition test [HAI]: HAI antibody titers will be measured by standard
microtiter assay (Admon et al., 1997). 12 HA units of the selected Influenza A vaccine
strain will be added to diluted pre-treated sera with receptor destroying enzyme (RDE, Sigma
MO) and heat inactivation. Following incubation, washed chicken erythrocytes will be added
until sedimentation ensues in the control wells. HAI titer is the inverse of highest
dilution of serum exhibiting complete HAI.
Influenza-specific IgG and sIgA ELISA: Influenza virus A specific IgG in serum/plasma and
sIgA in colostrum, breast milk and infant nasal swab will be analyzed by ELISA as described
previously with minor modification (Bruhl et al., 2000; Greenbaum et al., 2004). Briefly
immunoplates will be coated with purified influenza antigen obtained from NIBSC at 2 ug/mL
for overnight at 40C. and then diluted samples will be added for another overnight
incubation. HRP-conjugated anti-human IgG (BD-Pharmingen, CA) or mouse anti-sIgA,
peroxidase-labeled (Alpco Diagnostics, NH) will be used as conjugates. To construct standard
curve, a serial dilution of pooled samples assigned with an arbitrary value will be
introduced in each ELISA plate. Total sIgA in colostrum, breast milk and infant nasal swab
will also be determined by EIA kit (Alpco Diagnostics) to adjust influenza A specific sIgA
response with respect to overall sIgA secretion.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention
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