H I V / A I D SM A J O R A R T I C L E
Safety and Immunogenicity of 2009 pH1N1
Vaccination in HIV-Infected Pregnant Women
Mark J. Abzug,1Sharon A. Nachman,2Petronella Muresan,3Edward Handelsman,4,aD. Heather Watts,5Terence Fenton,3
Barbara Heckman,6Elizabeth Petzold,7Adriana Weinberg,1,band Myron J. Levin1,b; for the International Maternal
Pediatric Adolescent AIDS Clinical Trials Group P1086 Protocol Teamc
1Department of Pediatrics, Infectious Diseases, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora;2Department of
Pediatrics, State University of New York Health Science Center at Stony Brook;3Statistical and Data Analysis Center, Center for Biostatistics in AIDS
Research, Harvard School of Public Health, Boston, Massachusetts;4Division of AIDS, National Institute of Allergy and Infectious Diseases, and
5Maternal and Pediatric Infectious Diseases Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda,
Maryland;6Frontier Science and Technology Research Foundation, Buffalo, New York; and7Social and Scientific Systems, Silver Spring, Maryland
nerability to 2009 pandemic H1N1 influenza (pH1N1) infection. The safety and immunogenicity of pH1N1 vac-
cination in HIV-infected pregnant women are unknown.
Methods.HIV-infected women 18–39 years of age and 14–34 weeks’ gestation on antiretroviral therapy re-
ceived two 30-μg doses of unadjuvanted, inactivated pH1N1 vaccine 21 days apart. Hemagglutination inhibition
titers were measured at entry, 21 days after dose 1, and 10 and 21 days after dose 2, and, in mothers and infants,
at delivery and 3 and 6 months postdelivery.
Results.No severe vaccine-related adverse events were observed among 127 subjects. At entry, 21% had seropro-
tective (≥1:40) titers. Seroprotection and seroresponse (≥4-fold rise) occurred in 73% and 66% after dose 1 and 80%
and 72% after dose 2, respectively. Of women lacking seroprotection at entry, 66% attained seroprotection after dose
1 and 75% after dose 2. Seroprotective titers were present in 67% of mothers and 65% of infants at delivery (median
66 days after dose 2), 60% of mothers and 26% of infants at 3 months postdelivery, and 59% of mothers and 12% of
infants at 6 months postdelivery.
Conclusions. Two 30-μg doses were moderately immunogenic in HIV-infected pregnant women. No concerning
vaccine-related safety signals were observed. Seroprotection persisted in most women postpartum. Efficient transplacental
antibody transfer occurred, but seroprotection in infants waned rapidly. Vaccination to protect HIV-infected pregnant
women and their newborns from new influenza strains is feasible, but more immunogenic platforms should be evaluated.
Clinical Trials Registration.NCT00992017.
Pregnant women infected with human immunodeficiency virus (HIV) may have particular vul-
Keywords.pH1N1; vaccine; HIV-infected; pregnancy; immunogenicity.
Early in the 2009 pH1N1 pandemic, it was recognized
that pregnant women were at high risk, with excess
hospital and intensive care unit admissions and an es-
timated 5-fold relative risk of death. Risk was particu-
larly associated with infection in the second and third
trimesters, extending to the second week postpartum
[1–6]. Similar patterns observed in previous influenza
pandemics and epidemics were thought to reflect im-
munological and physiological changes associated
with pregnancy . Additionally, maternal infection
with pH1N1 or seasonal influenza has been associated
with preterm labor, preterm delivery, and adverse
fetal/neonatal outcomes, and infection in young
Received 6 December 2012; accepted 24 January 2013; electronically published
1 February 2013.
bA. W. and M. J. L. contributed equally to this work.
cMembers of the International Maternal Pediatric Adolescent AIDS Clinical
Trials Group P1086 Protocol Team and participating sites are listed in the Notes.
Presented in part: 17th Conference on Retroviruses and Opportunistic Infec-
tions, San Francisco, CA, 16–19 February 2010. Abstract T-1002; and 48th Annual
Meeting of the Infectious Diseases Society of America, Vancouver, BC, Canada,
21–24 October 2010. Abstract LB-14.
Correspondence: Mark J. Abzug, MD, Pediatric Infectious Diseases, Children’s
Hospital Colorado, 13123 E 16th Ave, Box B055, Aurora, CO 80045 (mark.abzug@
Clinical Infectious Diseases2013;56(10):1488–97
© The Author 2013. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
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infants with an increased risk of severe illness and death [2, 3,
5, 7, 8].
A second group that had increased risk of hospitalization,
intensive care unit admission, and death in the 2009 pH1N1
pandemic was patients with medical comorbidities, including
immunocompromising conditions, which conferred an esti-
mated 16-fold relative risk of fatality [4, 9]. Although some
reports did not link human immunodeficiency virus (HIV)
infection to excess pH1N1 morbidity or death , others
demonstrated increased hospital admission rates among HIV-
infected populations [11, 12].
Women who are pregnant and HIV infected lie at the inter-
section of 2 high-risk conditions that, in combination, may
pose particular vulnerability to pH1N1 infection. This group
represents a high priority for vaccination to prevent maternal
morbidity and mortality, avert pregnancy complications, and
provide protection to infants in the first months of life before
they are eligible for vaccination. Although information is avail-
able on the immune response to pH1N1 vaccine in pregnancy
[5, 7, 8], none exists for HIV-infected pregnant women. Study
P1086 of the International Maternal Pediatric Adolescent
AIDS Clinical Trials (IMPAACT) group was designed to eval-
uate safety and immunogenicity of a pH1N1 vaccination
regimen in HIV-infected pregnant women.
HIV-infected women 18–39 years of age and between 14–34
weeks of gestation were enrolled at 31 US IMPAACT sites in
October–November 2009. Subjects were required to be on an-
tiretroviral therapy prior to or concomitantly with the first
visit. Exclusion criteria included allergy to eggs or other
vaccine components; history of severe reaction to seasonal
inactivated influenza vaccine; previous polymerase chain reac-
tion (PCR)–documented pH1N1 infection or positive influen-
za test between June 2009 and screening; previous pH1N1
vaccination; any recent vaccination, nonlicensed medication,
or blood product; acute illness or fever; neoplastic or immuno-
suppressive disease (other than HIV infection); immunosup-
pressive treatment including corticosteroids in the preceding 3
months; personal or family history of Guillain-Barré syn-
drome; and onset of neurologic disease in the preceding 6
months. Informed consent was obtained in accordance with
the guidelines of the US Department of Health and Human
Services and participating institutions.
Unadjuvanted, inactivated pH1N1 monovalent vaccine (Flu-
virin, Novartis, Basel, Switzerland), 30 μg/dose (2 standard
15 μg/0.5 mL injections, intramuscularly, 1 per upper extremity
or at least 2 inches apart in the same upper extremity), was
given at entry. Subjects who did not experience a grade ≥3
adverse event or develop any condition that would have led
to study exclusion received a second 30-μg dose on day 21
(+7 days). A 2 double-dose regimen was chosen to optimize
immunogenicity. The second dose was temporarily deferred
for acute illness, recent infection, or steroid treatment. Subjects
who delivered prior to the second dose received the second
dose after delivery. Inactivated seasonal influenza vaccine (not
containing pH1N1) was permitted ≥14 days prior to the first
dose or ≥21 days after the second dose of pH1N1 vaccine.
Adverse events were assessed by a symptom diary and tele-
phone contact or clinic visits on days 2, 10, and 21 after each
vaccination; at delivery; and at 3 and 6 months after delivery.
Clinic visits occurred within 72 hours of fever or symptoms of
an influenza-like illness and within 24 hours of onset of lower
extremity weakness, hand/feet tingling, or difficulty walking.
Respiratory specimens were obtained at fever/influenza-like
Maternal pH1N1 hemagglutination inhibition (HAI) titers
were measured as previously described , at entry, 21 days
after dose 1; 10 and 21 days after dose 2; at delivery; and at 3
months after delivery. Infant HAI titers were measured at
birth (cord blood or infant blood obtained within 7 days of
delivery) and at 3 months. Maternal and infant titers were
measured at 6 months after delivery in a subset of mother–
infant pairs who received both doses of vaccine and had
complete sets of samples prior to delivery. HAI titers were
expressed as the reciprocal of the endpoint titer. Titers <10
were considered undetectable and were assigned values of
5. Seroprotection, defined as titer ≥40; geometric mean titers
(GMTs); seroresponse, defined as a ≥4-fold rise in titer
from baseline following vaccination; and complete response,
defined as attaining seroprotection and seroresponse, were
Sample Size and Statistical Analysis
The accrual target was 130 subjects to obtain at least 100
mothers who received 2 vaccine doses and had complete sets
of specimens prior to delivery, which would provide ≥95%
probability of detecting an adverse event with a population in-
cidence of ≥3% and confidence intervals of ±9% or less for
vaccine response rates. Antibody responses after the first vac-
cination were analyzed for subjects with available data who
received the first vaccine dose and had the day 21 postvaccine
dose 1 visit prior to delivery. Responses 10 and 21 days after
the second vaccination were analyzed for women with avail-
able data who received both doses of vaccine and had the re-
spective visits prior to delivery. Exact McNemar test was used
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