Madhi 2014 Influenza Vaccination of Pregnant Women and Protection of Their Infants

The n e w e ng l a n d j o u r na l of m e dic i n e
Original Article
Influenza Vaccination of Pregnant Women

and Protection of Their Infants
Shabir A. Madhi, M.D., Ph.D., Clare L. Cutland, M.D., Locadiah Kuwanda, M.Sc.,
Adriana Weinberg, M.D., Andrea Hugo, M.D., Stephanie Jones, M.D.,
Peter V. Adrian, Ph.D., Nadia van Niekerk, B.Tech., Florette Treurnicht, Ph.D.,
Justin R. Ortiz, M.D., Marietjie Venter, Ph.D., Avy Violari, M.D.,
Kathleen M. Neuzil, M.D., Eric A.F. Simões, M.D., Keith P. Klugman, M.D., Ph.D.,
and Marta C. Nunes, Ph.D., for the Maternal Flu Trial (Matflu) Team*
A BS T R AC T
BACKGROUND
The authors’ affiliations are listed in the There are limited data on the efficacy of vaccination against confirmed influenza
Appendix. Address reprint requests to in pregnant women with and those without human immunodeficiency virus (HIV)
Dr. Madhi or Dr. Nunes at the Respirato-
ry and Meningeal Pathogens Research infection and protection of their infants.
Unit, Chris Hani Rd., Chris Hani–Baragwa-
nath Hospital, New Nurses Residence– METHODS
1st Fl. West Wing, Bertsham, Gauteng We conducted two double-blind, randomized, placebo-controlled trials of trivalent
2013, South Africa, or at shabirm@nicd inactivated influenza vaccine (IIV3) in South Africa during 2011 in pregnant women
.ac.za or [email protected].
infected with HIV and during 2011 and 2012 in pregnant women who were not
*A complete list of investigators in the infected. The immunogenicity, safety, and efficacy of IIV3 in pregnant women and
Matflu Trial is available in the Supple-
mentary Appendix, available at NEJM.org. their infants were evaluated until 24 weeks after birth. Immune responses were
measured with a hemagglutination inhibition (HAI) assay, and influenza was diag-
Drs. Madhi and Nunes contributed equal-
ly to this article. nosed by means of reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assays
of respiratory samples.
N Engl J Med 2014;371:918-31.
DOI: 10.1056/NEJMoa1401480
RESULTS
Copyright © 2014 Massachusetts Medical Society.
The study cohorts included 2116 pregnant women who were not infected with HIV
and 194 pregnant women who were infected with HIV. At 1 month after vaccina-
tion, seroconversion rates and the proportion of participants with HAI titers of
1:40 or more were higher among IIV3 recipients than among placebo recipients in
both cohorts. Newborns of IIV3 recipients also had higher HAI titers than new-
borns of placebo recipients. The attack rate for RT-PCR–confirmed influenza among
both HIV-uninfected placebo recipients and their infants was 3.6%. The attack
rates among HIV-uninfected IIV3 recipients and their infants were 1.8% and 1.9%,
respectively, and the respective vaccine-efficacy rates were 50.4% (95% confidence
interval [CI], 14.5 to 71.2) and 48.8% (95% CI, 11.6 to 70.4). Among HIV-infected
women, the attack rate for placebo recipients was 17.0% and the rate for IIV3 re-
cipients was 7.0%; the vaccine-efficacy rate for these IIV3 recipients was 57.7%
(95% CI, 0.2 to 82.1).
CONCLUSIONS
Influenza vaccine was immunogenic in HIV-uninfected and HIV-infected pregnant
women and provided partial protection against confirmed influenza in both groups
of women and in infants who were not exposed to HIV. (Funded by the Bill and
Melinda Gates Foundation and others; ClinicalTrials.gov numbers, NCT01306669
and NCT01306682.)
918 n engl j med 371;10 nejm.org September 4, 2014
The New England Journal of Medicine

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Copyright © 2014 Massachusetts Medical Society. All rights reserved.
P
regnant women are designated as a HIV infection and the other involving pregnant
priority group for seasonal influenza vac- women with HIV infection, to evaluate the safety,
cination by the World Health Organization immunogenicity, and efficacy of IIV3 in these
(WHO)1 because of their heightened susceptibil- women and in their infants until 24 weeks post
ity to severe influenza from the second trimester partum.
to the early postpartum period.2,3 Since pregnancy
is associated with immunomodulation, including Me thods
the attenuation of cell-mediated immune re-
sponses,4 the efficacy of inactivated influenza Study Design, Objectives, and Oversight
vaccine (IIV) in pregnant women may differ The two studies were randomized, double-blind,
from its efficacy in healthy nonpregnant women placebo-controlled trials conducted in Soweto,
and in men.5 This difference in vaccine efficacy South Africa, where antenatal HIV testing is rou-
could be further accentuated in pregnant women tine. The enrollment of HIV-uninfected pregnant
infected with the human immunodeficiency vi- women was initiated at four antenatal clinics
rus (HIV), who are at heightened risk for severe before the onset of the 2011 influenza season
influenza illness6-8 because of HIV-related immu- (March 3 through August 4) and the 2012 season
nosuppression.9-14 (March 6 through July 2). Members of the HIV-
Reduced attack rates for all-cause febrile re- infected cohort were enrolled at the same facili-
spiratory illness among women vaccinated against ties (March 3 through June 2, 2011). Eligibility
influenza during pregnancy were observed dur- criteria for both cohorts included an age of 18 to
ing the 1957 Asian influenza pandemic in the 38 years, an estimated gestation of 20 to 36 weeks,
United States and in a later randomized, con- and the ability to understand and comply with
trolled trial in Bangladesh.15,16 A recent case–con- planned study procedures. (The methods used to
trol study in the United States also reported that determine gestational age and the exclusion cri-
pregnant women with influenza confirmed by teria are provided in the Supplementary Appen-
means of reverse-transcriptase–polymerase-chain- dix, which is available with the full text of this
reaction (RT-PCR) assay (hereafter referred to as article, along with the original and final protocols,
confirmed influenza) were 44 to 53% less likely at NEJM.org.) All HIV-infected mother–infant dy-
to have been vaccinated with trivalent IIV (IIV3) ads in 2011 and a subset of HIV-uninfected dyads
than controls who did not have influenza.17 To were included in a nested immunogenicity study
our knowledge, no published randomized, con- that was performed during each year of the trial.
trolled trial has assessed the efficacy of IIV in The primary objectives for the cohort of women
preventing confirmed influenza in pregnant without HIV infection were to evaluate the effi-
women with HIV infection and those without HIV cacy of IIV3 vaccination during pregnancy in
infection.18,19 protecting their infants against confirmed influ-
The vaccination of pregnant women may also enza through 24 weeks of age and to compare
confer partial protection against confirmed in- seroconversion rates between IIV3 recipients and
fluenza in their infants, as reported in the Ban- placebo recipients 1 month after vaccination. Sec-
gladeshi trial (in which infants whose mothers ondary objectives included measuring vaccine ef-
had been vaccinated with IIV3 were 63% less ficacy against confirmed influenza in all women
likely to have influenza [confirmed by means of until 24 weeks post partum. In the HIV-infected
enzyme-linked immunosorbent assay]).16 How- cohort, an additional primary objective was to
ever, observational studies have had conflicting evaluate the immunogenicity of IIV3 in the wom-
results with regard to the efficacy of IIV3 vacci- en. Secondary objectives for this cohort included
nation during pregnancy in protecting infants measuring vaccine efficacy against confirmed
against all-cause respiratory illness.20-23 The pro- influenza in the women and their infants until
tection of infants 6 months of age or younger 24 weeks post partum. Additional secondary ob-
against influenza is a public health priority. These jectives for both cohorts are listed in the Supple-
infants are at high risk for influenza-associated mentary Appendix.
hospitalization, and their immune responses to The studies were approved by the Human
IIV vaccination are poor.24-26 We conducted two Research Ethics Committee of the University of
studies, one involving pregnant women without the Witwatersrand and were conducted in accor-
n engl j med 371;10 nejm.org September 4, 2014 919

dance with Good Clinical Practice guidelines. enza virus by means of an RT-PCR assay. The labo-
Written informed consent was obtained from all ratory methods used for sample collection, in-
participants. All the authors vouch for the fidel- fluenza-virus identification, and genotyping are
ity of this report to the protocols and the com- detailed in the Supplementary Appendix.
pleteness of the data and analyses. The funders
did not participate in the conduct of the study, Safety
data collection, analyses of the data, or the writ- Women enrolled in the nested immunogenicity
ing of the manuscript. subsets were provided with diary cards on which
to document possible local and systemic reac-
Randomization and Study Treatment tions to vaccination for 1 week. Digital thermom-
Participants were randomly assigned in a 1:1 ratio eters were provided to measure oral temperature
to receive IIV3 or placebo. Randomization was in women and axillary temperature in infants
performed by the study statistician with the use of after vaccination and during illness. Serious ad-
computer-generated assignments. With the excep- verse events were recorded and graded through-
tion of the statistician and the pharmacist, study out the study period with the use of an estab-
personnel were unaware of the group assign- lished system.29
ments, as were the study participants.
Influenza vaccine (Vaxigrip, lot number G05831 Statistical Analysis
in 2011 and H7221-2 in 2012; Sanofi Pasteur) In the HIV-uninfected cohort, the sample size was
was purchased by the study team. The vaccine based on the primary outcome of vaccine efficacy
contained 15 μg each of A/California/7/2009 in the infants. The sample size for the HIV-unin-
(A/[H1N1]pdm09), A/Victoria/210/2009 (A/H3N2), fected cohort was outcome-driven. We aimed at
and a B/Brisbane/60/2008–like virus (B/Victoria), identifying at least 27 cases of confirmed illness
as recommended by WHO for the Southern Hemi- caused by influenza virus in infants up to 24 weeks
sphere in 2011 and 2012.27,28 The study pharma- of age in order to detect a 70% reduction in con-
cist used a 2-ml syringe to draw 0.5 ml of vaccine firmed influenza among the infants, with 80%
for the women receiving IIV3 and 0.5 ml of sterile power. The sample size required for the HIV-
0.9% normal saline solution for the women re- infected cohort was 180 participants, which pro-
ceiving placebo. The two preparations were mac- vided 90% power to detect a difference of at least
roscopically indistinguishable. The vaccines were 67% in rates of seroconversion to individual vac-
administered into the deltoid muscle by study staff. cine strains between IIV3 recipients and placebo
recipients.
Serologic Efficacy and Immunogenicity The immunogenicity analyses included com-
In 2011 and 2012, all mothers and infants in the parisons of geometric mean titers between study
HIV-infected cohort and a nested group of 180 groups and of the increase in titers from base-
HIV-uninfected mother–infant dyads were enrolled line to 1 month after vaccination. We performed
in an intensive safety and immunogenicity study. a two-sided, two-sample t-test and calculated the
The timing of blood-sample collection and pro- corresponding 95% confidence intervals for the
cessing, the method used for antibody testing titers, using logarithmic transformation for all
(hemagglutination inhibition [HAI]), and the stan- values. Post-vaccination analyses of immune re-
dard criteria used to qualify HAI results as sero- sponse were adjusted for baseline HAI titers and
conversion and as seroprotective or seronegative between-group differences in baseline character-
titers are provided in the Supplementary Appendix. istics. The proportions of participants in each
group who underwent seroconversion and the
Vaccine Efficacy proportions of participants who had local or sys-
Active surveillance for influenza-like illness (as temic reactions were compared by means of chi-
defined in the protocols) was conducted through square or Fischer’s exact tests. Vaccine efficacy
weekly contact with participants (see the Supple- was calculated with the use of the formula (1–IL)/
mentary Appendix for details). Women and infants IP, where IL is the case incidence rate in the vac-
identified as having influenza-like illness, and cinated group and IP is the case incidence rate in
those unexpectedly presenting with or hospitalized the placebo group; 95% confidence intervals were
for any respiratory illness, were tested for influ- calculated and between-group differences were

tested. Estimates of vaccine efficacy were adjusted We enrolled 194 pregnant women who were in-
for differences in maternal age and status with fected with HIV; 100 were randomly assigned to
respect to antiretroviral treatment at enrollment, the group vaccinated with IIV3 and 94 to the
which were prevalent in the HIV-infected cohort. placebo group (Fig. S2 in the Supplementary Ap-
For vaccine efficacy end points, data were cen- pendix). The mean maternal age at enrollment was
sored after the first episode of a specific clinical 28.2 years, and the mean gestational age was
outcome. Between-group differences in the time 27.3 weeks (Table 2). The baseline median CD4+
to a first episode of confirmed influenza were T-cell count in the HIV-infected women was 393.5
compared in survival analyses by means of the cells per cubic millimeter; 12.6% of the women
log-rank test. (24 of 190) had counts of less than 200 cells per
The intention-to-treat analyses included mater- cubic millimeter. The median level of plasma
nal outcomes from receipt of vaccine or placebo HIV-1 RNA was 1067 copies per milliliter; 23.0%
to 175 days after birth and infant outcomes from of the women (43 of 187) had undetectable levels
birth to 175 days of age. The per-protocol analyses of HIV-1 RNA. There were 100 live births in the
included maternal outcomes that occurred 14 or group vaccinated with IIV3 and 88 live births in
more days after receipt of vaccine or placebo; per- the placebo group among the 183 HIV-infected
protocol analyses of outcomes for infants were women who remained in the study until delivery.
limited to those born at least 28 days after their
mother’s vaccination, those whose gestational age Immunogenicity of the Vaccine
at birth was at least 37 weeks, or those who had HIV-Uninfected Cohort
a birth weight of at least 2500 g. The per-protocol Of the 376 participants in the immunogenicity
immunogenicity analysis was limited to women subset, 142 IIV3 recipients and 148 placebo recipi-
from whom a blood sample was obtained 28 to 35 ents were included in the per-protocol analysis
days after vaccination and to infants from whom of immunogenicity (Fig. S3 and Table S1 in the
a blood sample was obtained within 7 days after Supplementary Appendix). Post-vaccination geo-
birth and who had a gestational age of at least 37 metric mean titers increased from baseline by a
weeks at birth or a birth weight of at least 2500 g. factor of 6 to 10 in IIV3 recipients and were sig-
An exploratory analysis was performed with the nificantly higher for all three vaccine strains, as
use of extended windows for obtaining blood compared with titers in placebo recipients (Ta-
samples after vaccination (28 to 42 days) and after ble 3). Seroconversion rates for strains A(H1N1)
delivery (up to 14 days). pdm09, A(H3N2), and B(Victoria) among IIV3 re-
Study data were collected and managed with cipients were 72.5%, 64.8%, and 92.3%, respec-
the use of Research Electronic Data Capture tively; rates among placebo recipients were 8.1%,
(REDCap), version 5.9.13.30 All statistical analyses 2.7%, and 2.0%, respectively (P<0.001 for all com-
were conducted with the use of Stata software, parisons). A greater proportion of IIV3 recipients
version 12.1. All P values were two-sided, and a had seroprotective HAI titers after vaccination,
value of 0.05 or less was considered to indicate as compared with placebo recipients (Table 3).
statistical significance. Newborns of IIV3 recipients had higher HAI
geometric mean titers for all vaccine strains than
did newborns of placebo recipients and were also
R e sult s
more likely to have an HAI titer of 1:40 or higher
Baseline Characteristics of the Study for A/(H1N1)pdm09 (81.1% vs. 34.0%), A(H3N2)
Participants (60.0% vs. 17.5%), and B(Victoria) (82.1% vs.
We enrolled 2116 black African pregnant women 43.7%) (P<0.001 for all comparisons) (Table 3). The
who were not infected with HIV; 1062 were ran- ratios of HAI titers in newborns to maternal ti-
domly assigned to the group vaccinated with IIV3 ters were 0.7 to 1.0 for the three vaccine strains
and 1054 to the group that received placebo. There and were similar between study groups, with the
were 1026 live infants born to IIV3 recipients and exception of higher ratios for B/Victoria in the
1023 live infants born to placebo recipients (Fig. S1 placebo group (Table 3). Similar findings were
in the Supplementary Appendix). The mean ma- observed in the immunogenicity analyses when the
ternal age at enrollment was 26.2 years, and the window for obtaining blood samples was extended
mean gestational age was 26.8 weeks (Table 1). (Tables S2 and S3 in the Supplementary Appendix).

Table 1. Baseline Characteristics of HIV-Uninfected Pregnant Women, Fetal Outcomes, and Newborn Characteristics.*
Characteristic or Outcome Overall IIV3 Placebo

Women
Total no. of women 2116 1062 1054
Mean age — yr 26.2±5.3 26.4±5.3 25.9±5.3
Body-mass index†
Median 27.6 28.0 27.4
Interquartile range 24.3–31.9 24.6–32.1 24.1–31.6
Mean gestational age at enrollment — wk 26.8±4.4 26.7±4.4 26.9±4.4
Gravidity
Median 2.0 2.0 2.0
Parity
Median 1.0 1.0 1.0
Fetuses and newborns
Total no. of known outcomes 2081 1044 1037
Miscarriage, gestational age <28 wk — no. (%)‡ 8 (0.4) 3 (0.3)§ 5 (0.5)
Stillbirth, gestational age ≥28 wk — no. (%)‡ 24 (1.2) 15 (1.4) 9 (0.9)
Live birth — no. (%) 2049 (98.5) 1026 (98.3) 1023 (98.7)
Twin birth — no. (%) 110 (5.3) 60 (5.7) 50 (4.8)
Type of delivery — no. (%)
Normal vaginal delivery 1393 (66.9) 700 (67.0) 693 (66.8)
Cesarian section 656 (31.5) 326 (31.2) 330 (31.8)
Preterm birth, gestational age <37 wk — no. (%)¶ 204 (10.0) 108 (10.5) 96 (9.4)
Overall birth weight — kg¶‖**
Median 3.1 3.1 3.1
Range 0.5–4.8 0.5–4.6 0.7–4.8
Birth weight of infants born during influenza season — kg¶**††
Median 3.1 3.1 3.1
Range 0.4–4.8 0.6–4.6 0.4–4.8
Birth weight of <2500 g — no. (%)¶‖** 255 (12.5) 133 (13.0) 122 (12.0)
Death after delivery — no. (%)¶‡‡ 22 (1.1) 12 (1.2) 10 (1.0)
Admission to neonatal nursery — no. (%)¶ 142 (6.9) 71 (6.9) 71 (6.9)
* Plus–minus values are means ±SD. HIV denotes human immunodeficiency virus, and IIV3 trivalent inactivated influ-
enza vaccine.
† The calculations for body-mass index (the weight in kilograms divided by the square of the height in meters) were
based on 796 women in the IIV3 group and 789 women in the placebo group.
‡ Details on miscarriages and stillbirths are provided in Table S9 in the Supplementary Appendix.
§ This number includes one medically assisted termination of pregnancy.
¶ Numbers and percentages are based on live births.
‖ Numbers are based on 1024 observations in the IIV3 group and 1021 observations in the placebo group.
** No significant difference in birth weight between the study groups was observed, even when weight was stratified
according to sex.
†† Numbers are based on 857 observations in the IIV3 group and 874 observations in the placebo group.
‡‡ Further details on newborn deaths are provided in Table S10 in the Supplementary Appendix.

HIV-Infected Cohort fants of placebo recipients were A/H3N2 (14 in-

The demographic characteristics of HIV-infected fants [37%]), B/Victoria (11 [29%]), and B/Yamagata
women included in the per-protocol analysis of (12 [32%]). Among infants with confirmed in-
immunogenicity (Fig. S2 in the Supplementary fluenza, the numbers infected with the influen-
Appendix) are shown in Table S4 in the Supple- za virus strain carried by their mothers were as
mentary Appendix. The receipt of IIV3 resulted in follows: 1 of 19 infants in the IIV3 group (5.3%)
increases in geometric mean titers of antibodies and 11 of 37 in the placebo group (29.7%, P = 0.04).
to A/(H1N1)pdm09, A/H3N2, and B/Victoria by The vaccine efficacy estimates in the per-proto-
factors of 2.9, 2.4, and 3.2, respectively, and se- col analysis were similar to the estimates in the
roconversion rates of 42.9%, 35.7%, and 40.0%, intention-to-treat analysis for the women and
respectively. Furthermore, as compared with pla- their infants (Table S8 in the Supplementary Ap-
cebo recipients, a higher proportion of IIV3 recipi- pendix).
ents had seroprotective HAI titers after vaccina-
tion (Table S5 in the Supplementary Appendix). HIV-Infected Cohort
The newborns of IIV3 recipients had higher In the cohort of HIV-infected mothers, the at-
HAI geometric mean titers than did the newborns tack rate was lower among IIV3 recipients than
of placebo recipients. The ratio of geometric mean among placebo recipients (7.0% vs. 17.0%), indicat-
HAI titers ranged between 0.7 and 1.4; ratios ing an adjusted vaccine efficacy of 57.7% (95% CI,
were higher in the placebo group for A/(H1N1) 0.2 to 82.1) (Table 4 and Fig. 1). The attack rates
pdm09 (P = 0.05) and A/H3N2 (P = 0.01). In the IIV3 were 5.0% and 6.8% among infants of IIV3 re-
group, the proportion of newborns with an HAI cipients and infants of placebo recipients, respec-
titer of 1:40 or higher was 60.7% for A/(H1N1) tively (vaccine efficacy, 26.7%; P = 0.60) (Table 4
pdm09, 42.9% for A/H3N2, and 78.6% for B/Vic- and Fig. 1). In 6 of 11 infants of HIV-infected
toria; titers for all three strains were higher than mothers with confirmed influenza (55%), in-
those in the placebo group (Table S5 in the Sup- cluding 2 infants whose mothers received IIV3,
plementary Appendix). Similar findings were ob- the mothers were infected with the same strain
served in the immunogenicity analyses when ex- as their infants. Estimates of vaccine efficacy
tended windows for obtaining blood samples were among HIV-infected women and their infants were
used (Tables S6 and S7 in Supplementary Ap- similar in the per-protocol and intention-to-treat
pendix). analyses (Table S8 in the Supplementary Appendix).
Vaccine Efficacy Safety

HIV-Uninfected Cohort The details of solicited local and systemic reac-
The attack rates for confirmed influenza among tions in the HIV-uninfected cohort and the HIV-
placebo recipients and IIV3 recipients were 3.6% infected cohort are shown in Tables S9 and S10 in
and 1.8%, respectively, indicating a vaccine effi- the Supplementary Appendix. Injection-site reac-
cacy of 50.4% (95% confidence interval [CI], 14.5 tions (mainly mild to moderate) were more fre-
to 71.2) (Table 4 and Fig. 1). The vaccine efficacy quent among IIV3 recipients than among place-
was similar when determined according to the vac- bo recipients in both cohorts, but there were no
cine strain (46.1%; 95% CI, 6.4 to 69.0). For the other significant differences in solicited reac-
2 years of the study, the predominant strain of tions between the two study groups in either
influenza virus circulating among placebo recipi- cohort. Data on serious adverse events in both
ents was A/H3N2 (57.9%), for which an exploratory cohorts, including infant and maternal deaths
analysis identified a vaccine efficacy of 57.5% and hospitalizations, are shown in Tables S11 to
(95% CI, 7.6 to 80.4). S23 in the Supplementary Appendix. There were
The attack rate was lower among infants whose no significant between-group differences with
mothers were IIV3 recipients (1.9%) than among regard to rates of miscarriage, stillbirth, or pre-
those whose mothers were placebo recipients mature birth or birth weight in the HIV-uninfect-
(3.6%), indicating a vaccine efficacy of 48.8% ed cohort (Table 1, and Table S11 in the Supple-
(95% CI, 11.6 to 70.4) (Table 4 and Fig. 1). The mentary Appendix) and in the HIV-infected cohort
predominant strains causing illness in the 38 in- (Table 2). The findings were similar in an analy-

Table 2. Baseline Characteristics of HIV-Infected Pregnant Women, Fetal Outcomes, and Newborn Characteristics.*

Women
Total no. of women 194 100 94
Mean age — yr 28.2±5.1 27.2±4.9† 29.2±5.1†
Mean body-mass index‡ 28.7±5.3 29.2±5.0 28.3±5.7
Mean gestational age at enrollment — wk 27.3±3.8 27.6±3.9 26.9±3.7
Gravidity
Median 2.0 2.0 2.0
Parity
Median 1.0 1.0 1.0
HAART — no. (%)
At enrollment 60 (30.9) 22 (22.0)† 38 (40.4)†
At delivery 77 (39.7) 33 (33.0) 44 (46.8)
ART for prevention of mother-to-child HIV transmission
— no. (%)
At enrollment 86 (44.3) 54 (54.0)† 32 (34.0)†
At delivery 87 (44.9) 52 (52.0)§ 35 (37.2)§
CD4+ T-lymphocyte count — cells/mm3
At enrollment¶
Median 393.5 410.0 379.0
At post-vaccination visit‖
Median 399.5 371.0 409.0
At delivery**
Median 446.5 441.0 508.0
HIV-1 viral load — copies/ml
At enrollment††
Median 1067.0 1679.0 399.0
Interquartile range 61.0–13,923.0 118.5–15,906.5 39.0–9990.0
At post-vaccination visit‡‡
Median 620.0 812.0§ 292.5§
Interquartile range 39.0–8278.0 130.0–13,221.0 39.0–3056.0
At delivery§§
Median 265.0 222.0 356.0
Fetuses and newborns
Total no. of live-born infants 188 100 88
Twin birth — no. (%) 10 (5.3) 6 (6.0) 4 (4.5)
Type of delivery — no. (%)
Normal vaginal 111 (59.0) 58 (58.0) 53 (60.2)
Cesarian section 77 (41.0) 42 (42.0) 35 (39.8)
Preterm birth, gestational age <37 wk — no. (%) 26 (13.8) 13 (13.0) 13 (14.8)

Table 2. (Continued.)

Overall birth weight — kg¶¶
Median 3.0 2.9 3.0
Range 0.8–4.3 0.8–4.3 1.9–4.0
Birth weight of infants born during influenza season — kg‖‖
Median 3.0 3.0 3.0
Range 0.8–4.3 0.8–4.3 1.9–4.1
Birth weight of <2500 g — no. (%)¶¶ 29 (15.6) 14 (14.1) 15 (17.2)
Death after delivery — no. (%)*** 4 (2.1) 2 (2.0) 2 (2.3)
Admission to neonatal nursery — no. (%) 9 (4.8) 6 (6.0) 3 (3.4)
* Plus–minus values are means ± SD. ART denotes antiretroviral therapy, and HAART highly active antiretroviral therapy.
† P<0.01.
‡ Data are based on 81 observations in the IIV3 group and 74 observations in the placebo group.
§ P<0.05.
¶ Numbers are based on 97 observations in the IIV3 group and 93 observations in the placebo group.
‖ Numbers are based on 78 observations in the IIV3 group and 68 observations in the placebo group.
** Numbers are based on 77 observations in the IIV3 group and 69 observations in the placebo group.
†† Numbers are based on 96 observations in the IIV3 group and 91 observations in the placebo group.
‡‡ Numbers are based on 77 observations in the IIV3 group and 64 observations in the placebo group.
§§ Numbers are based on 72 observations in the IIV3 group and 65 observations in the placebo group.
¶¶ Numbers and percentages are based on 99 observations in the IIV3 group and 87 observations in the placebo group.
‖‖ Numbers are based on 88 observations in the IIV3 group and 80 observations in the placebo group.
*** Further details on newborn deaths are provided in Table S17 in the Supplementary Appendix.
sis stratified according to sex and an analysis desh is prolonged and perennial, limiting the
limited to births that occurred during the influ- generalizability of the Bangladesh study to tem-
enza season. perate regions with more discrete influenza sea-
sons, such as South Africa.16 The effectiveness of
IIV3 vaccination in protecting the infants of preg-
Discussion
nant women not infected with HIV is further cor-
The trials of IIV3 efficacy in HIV-infected and roborated by case–control studies in the United
HIV-uninfected pregnant women showed a reduc- States among American Indians (in which most
tion in confirmed cases of influenza in both co- cases were diagnosed through serologic testing)
horts. Furthermore, we observed protection against and by a study of influenza-associated hospital-
confirmed influenza among infants of IIV3 re- ization in a large urban hospital (in which the di-
cipients who were not exposed to HIV, with a agnosis was confirmed through fluorescent anti-
similar trend observed in infants exposed to HIV. body testing).20,22
IIV3 was found to be safe, and the vaccine was It has been proposed that higher HAI titers may
immunogenic in HIV-uninfected women and HIV- be required to provide protection against influ-
infected women, supporting the current WHO enza in children; in adults, an HAI titer of 1:40
recommendations for influenza vaccination dur- or higher is associated with 50% protection.31,32,33
ing pregnancy.19 Nevertheless, in our study the proportion of
The vaccine efficacy against confirmed influ- HIV-unexposed newborns in the IIV3 group with
enza in infants who were not exposed to HIV HAI titers of 1:40 or higher (60 to 82%) suggests
(45.6%; 95% CI, 2.4 to 69.7) was similar to that that this threshold may be associated with ap-
reported in Bangladesh (63%; 95% CI, 5 to 85).16 proximately 50% protection against confirmed
However, direct comparisons with the results of influenza in such infants. Further studies and
the Bangladesh study are limited because of dif- analyses are warranted to establish a serocorrelate
ferences in the assays used for viral detection. In for the protection of HAI antibodies acquired
addition, influenza virus circulation in Bangla- through the placenta. Another way in which the

vaccination of pregnant women may protect their to influenza, even when the HIV infection is man-
infants against influenza involves prevention of the aged with antiretroviral treatment.
transmission of the virus to the infant by reduc- Extrapolation of the potential effect of influ-
ing the mother’s risk of influenza illness. This is enza vaccination in pregnancy solely on the basis
corroborated in part by our study, in which con- of HAI immune responses may be affected by
current confirmed influenza infection by homo- pregnancy-inducing immune tolerance, which
typic strains occurred more frequently in HIV- could influence vaccine effectiveness.4,5,36 The avail-
unexposed infants of placebo recipients than in ability of immunogenicity and efficacy data in our
HIV-unexposed infants of IIV3 recipients; infec- nested immunogenicity study helped to address
tions with homotypic strains also occurred con- this question. The proportions of HIV-uninfected
currently in 54.5% of the mothers of HIV-exposed IIV3 recipients with seroprotective HAI titers for
infants with confirmed influenza illness. A/(H1N1)pdm09, A/H3N2, and B/Victoria were
Unlike the study in Bangladesh, in which rates 93.3%, 78.0%, and 96.0%, respectively, with cor-
of clinical febrile respiratory illness were reduced responding overall vaccine efficacy against con-
by 29% and 36% in infants and mothers, respec- firmed influenza of 54.4%. These findings sug-
tively,16 our study did not show any reduction in gest that the threshold of 1:40 or higher was
the less specific outcomes of clinical influenza- predictive of an anticipated vaccine efficacy of
like illness or respiratory illness in either infants 50%, as proposed for healthy adults.31 Theoreti-
or mothers. The use of pneumococcal polysac- cally, the rate of naturally acquired immunity
charide vaccine as the comparator for the control among placebo recipients (20 to 45%) could have
group in the Bangladeshi study, as well as the use decreased the true efficacy of the vaccine, a con-
of different case definitions, may have contribut- sideration that would not be required in an im-
ed to the discrepant findings in the two studies. munologically naive placebo group of women not
Observational studies in the United States have infected with influenza.
also shown that maternal influenza vaccination Among IIV3 recipients in the HIV-infected co-
was not effective in protecting infants against all- hort, HAI titers of 1:40 or higher were observed
cause respiratory illness, indicating the lack of for A/H3N2 and A/(H1N1)pdm09 (48.6% and
specificity of such end points for the evaluation 68.6%, respectively). Consequently, the HAI titer
of influenza vaccine efficacy in infants.21,23 of 1:40 or higher, as a relative serocorrelate of pro-
The vaccine efficacy against confirmed influ- tection, would have paradoxically underestimat-
enza among HIV-uninfected women in our study ed vaccine efficacy against confirmed influenza
(per-protocol analysis, 54.4%; 95% CI, 19.5 to among the HIV-infected women (reported as
74.2) was similar to that reported in an observa- 70.6%). This observation is consistent with find-
tional study of vaccination against monovalent ings from our previous study involving HIV-infect-
A/(H1N1)pdm09 in pregnant Norwegian women ed adults.34 Among the HIV-infected cohort, IIV3
(70%; 95% CI, 66 to 75)33 and in a more recent did not affect the plasma HIV-1 viral load, mini-
case–control study in the United States (44 to mizing concern about the possibility of an in-
53%).17 The vaccine efficacy against confirmed increased risk of vertical transmission of HIV in
fluenza in HIV-infected pregnant women in our vaccinees.37,38
study (per-protocol analysis, 70.6%) was similar to One of the limitations of our study is the fact
that reported in a trial of IIV3 in South African that it was conducted at a single center; the gen-
HIV-infected men and women during the 2008 eralizability of the findings needs to be corrobo-
influenza epidemic (75.5%).34 The efficacy of the rated. Furthermore, the timing of enrollment was
vaccine in our study was also similar to that re- contingent on the commercial availability of IIV3.
ported in a meta-analysis of HIV-infected adults Although we initiated enrollment within 1 week
in high-income countries (66%; 95% CI, 36 to 82).35 after vaccine availability, vaccination extended
Notably, the attack rate among HIV-infected pla- into the influenza season, with some births oc-
cebo recipients in our study (17.0%) was greater curring after the influenza season. The difference
than that observed among HIV-uninfected pla- in duration of exposure to the influenza virus be-
cebo recipients (3.6%), a finding that highlights tween the women and their infants limited our
the greater susceptibility of HIV-infected persons ability to make a direct comparison of the attack

Table 3. Immune Responses to IIV3 Vaccine in HIV-Uninfected Pregnant Women and Transplacental Transfer of Antibodies to Newborns.*
Measure A(H1N1)pdm09 A/H3N2 B/Victoria
IIV3 Placebo P Value† IIV3 Placebo P Value† IIV3 Placebo P Value†

Mothers
Total no. of mothers 142 148 142 148 142 148
Geometric mean HAI titer
(95% CI)
Before vaccination 30.7 (25.5–37.0) 27.2 (21.8–34.0) 0.41 14.6 (124–17.0) 14.0 (11.8–16.6) 0.74 17.6 (15.6–19.9) 15.4 (13.4–17.7) 0.15
After vaccination 213.4 (175.7–259.2) 29.1 (23.0–36.8) <0.001 87.8 (70.5–109.2) 16.0 (13.3–19.1) <0.001 175.5 (148.7–207.3) 16.9 (14.6–19.6) <0.001
P value‡ <0.001 0.30 <0.001 0.005 <0.001 0.05
Factor increase in geometric mean 6.9 (5.6–8.6) 1.1 (0.9–1.2) <0.001 6.0 (4.9–7.4) 1.1 (1.0–1.2) <0.001 10.0 (8.4–11.8) 1.1 (1.0–1.2) <0.001
HAI titer (95% CI)
HAI titer ≥1:40 — no. (%);
(95% CI)
Before vaccination 73 (51.4); 66 (44.6); 0.73 33 (23.2); 37 (25.0); 0.25 29 (20.4); 30 (20.3); 0.97
(42.9–59.9) (36.4–53.0) (16.6–31.1) (18.3–32.8) (14.1–27.7) (14.1–28.0)
After vaccination 133 (93.7); 71 (47.8); <0.001 112 (78.9); 40 (27.0); <0.001 138 (97.2); 43 (29.1); <0.001
(88.3–97.1) (40.4–57.0) (71.2–85.3) (20.1–35.0) (92.9–99.2) (21.9–37.1)
P value‡ 0.006 0.37 0.001 0.43 <0.001 <0.001
Seroconversion 1 mo after vaccina- 103 (72.5); 12 (8.1); <0.001 92 (64.8); 4 (2.7); <0.001 131 (92.3); 3 (2.0); <0.001
tion — no. (%); (95% CI) (64.4–79.7) (4.3–13.7) (56.3–72.6) (0.7–6.8) (86.6–96.1) (0.4–5.8)

Newborns
n engl j med 371;10 nejm.org September 4, 2014

Total no. of newborns 95 103 95 103 95 103
Geometric mean HAI titer at ≤7 93.3 (71.1–122.4) 17.2 (13.8–22.7) <0.001 41.8 (31.6–55.3) 12.7 (10.6–15.1) <0.001 80.6 (64.9–100.1) 21.4 (17.8–25.7) <0.001
days of age (95% CI)

Ratio of newborn to maternal HAI 0.7 (0.6–0.8) 0.7 (0.6–0.8) 0.78 0.7 (0.6–0.9) 0.7 (0.6–0.8) 0.49 0.8 (0.7.–0.9) 1.0 (0.9–1.2) 0.04
titer (95% CI)§
HAI titer ≥1:40 at <7 days of age 77 (81.1); 35 (34.0); <0.001 57 (60.0); 18 (17.5); <0.001 78 (82.1); 45 (43.7); <0.001
— no. (%); (95% CI)¶ (71.7–88.4) (24.9–44.0) (49.4–69.9) (10.7–26.2) (72.9–89.2) (33.9–53.8)
* HAI denotes hemagglutination inhibition.
† These P values are for the comparison of the IIV3 and placebo groups.
‡ These P values are for the comparison of values within a group before and after vaccination.
§ The ratio of the newborn HAI titer to the maternal HAI titer was based on 93 observations in the IIV3 group and 102 observations in the placebo group.
¶ P values were adjusted for the mean number of days from maternal vaccination to birth.
927
928
Table 4. Efficacy of IIV3 Vaccination in Mothers and Infants until 24 Weeks after Birth, Intention-to-Treat Population.*
Efficacy End Point HIV-Uninfected Cohort HIV-Infected Cohort
IIV3 Placebo Vaccine IIV3 Placebo Vaccine

(N = 1026) (N = 1023) Efficacy P Value (N = 100) (N = 88) Efficacy P Value
Infants
RT-PCR–confirmed influenza —
no. (%); (95% CI)
With inclusion of B/Yamagata 19 (1.9); 37 (3.6); 48.8 (11.6 to 70.4) 0.01 5 (5.0); 6 (6.8); 26.7 (−132.0 to 76.8) 0.60
(1.1 to 2.9)† (2.6 to 5.0)†‡ (1.6 to 11.3)§ (2.5 to 14.3)§
With exclusion of B/Yamagata 13 (1.3); 25 (2.4); 48.2 (−0.8 to 73.3) 0.05 4 (4.0); 3 (3.4); 14.8 (−270.4 to 80.4) 0.57
(0.7 to 2.2) (1.6 to 3.6) (1.1 to 9.9) (0.7 to 9.6)
Influenza-like illness — no. (%); 595 (58.0); 584 (57.1); −1.6 (−9.4 to 5.7) 0.68 66 (66.0); 57 (64.8); −1.9 (−25.5 to 17.3) 0.86
(95% CI) (54.9 to 61.0) (54.0 to 60.1) (55.8 to 75.2) (53.9 to 74.7)
Any respiratory illness — no. (%); 706 (68.8); 697 (68.1); −1.0 (−7.1 to 4.8) 0.74 76 (76.0); 70 (79.5); 4.5 (−11.3 to 18.0) 0.56
The
(95% CI) (65.9 to 71.6) (65.2 to 71.0) (66.4 to 84.0) (69.6 to 87.4)
IIV3 Placebo Vaccine IIV3 Placebo Vaccine
(N = 1062) (N = 1054) Efficacy P Value (N = 100) (N = 94) Efficacy P Value
Women
RT-PCR confirmed influenza —
no. (%)
With inclusion of B/Yamagata 19 (1.8); 38 (3.6); 50.4 (14.5 to 71.2) 0.010 7 (7.0); 16 (17.0); 57.7 (0.2 to 82.1) 0.05
(1.1 to 2.8)¶ (2.6 to 4.9)¶ (2.9 to 13.9)‖ (10.1 to 26.2)‖
With exclusion of B/Yamagata 19 (1.8); 35 (3.3); 46.1 (6.4 to 69.0) 0.03 7 (7.0); 13 (13.8); 48.2 (−27.0 to 78.8) 0.15
(1.1 to 2.8) (2.3 to 4.6) (2.9 to 13.9) 7.6 to 22.5
n e w e ng l a n d j o u r na l
Influenza-like illness — no. (%) 175 (16.5); 181 (17.2); 4.0 (−16.0 to 20.6) 0.67 24 (24.0); 27 (28.7); −0.07 (−63.7 to 38.8) 0.99

of
(14.3 to 18.8) (14.9 to 19.6) (16.0 to 33.6) (19.9 to 39.0)

Any respiratory illness — no. (%) 674 (63.5); 687 (65.2); 2.6 (−3.7 to 8.6) 0.41 72 (72.0); 73 (77.7); 5.2 (−12.2 to 19.8) 0.54
(60.5 to 66.4) (62.2 to 68.1) (62.1 to 80.5) (67.9 to 85.6)
n engl j med 371;10 nejm.org September 4, 2014

* Vaccine efficacy in HIV-infected women was adjusted for maternal age and status with respect to antiretroviral treatment at enrollment. RT-PCR denotes reverse-transcriptase–poly-

merase-chain-reaction.
m e dic i n e
† Among HIV-unexposed infants of IIV3 recipients and placebo recipients, there were 0 and 1 cases of infection with A/(H1N1)pdm09, 7 and 14 cases of infection with A/H3N2, 6 and
11 cases of infection with B/Victoria, and 6 and 12 cases of infection with B/Yamagata, respectively.
‡ One baby born to a placebo recipient had a single influenza episode during which both A/(H1N1)pdm09 and A/H3N2 were detected.
§ Among HIV-exposed infants of IIV3 recipients and placebo recipients, infection with A/(H1N1)pdm09 occurred in 2 and 0 infants, respectively, infection with A/H3N2 occurred in
2 infants in each group, infection with B/Victoria occurred in 0 and 1 infants, respectively, and infection with B/Yamagata occurred in 1 and 3 infants, respectively.
¶ Among HIV-uninfected IIV3 recipients and placebo recipients, there were 5 and 6 cases of influenza virus strain A/(H1N1)pdm09, 10 and 22 cases of A/H3N2, 4 and 7 cases of B/
Victoria, and 0 and 3 cases of B/Yamagata, respectively.
‖ Among HIV-infected IIV3 recipients and placebo recipients, there were 6 and 8 cases of influenza virus strain A/(H1N1)pdm09, 1 and 4 cases of A/H3N2, 0 and 1 case of B/Victoria,
and 0 and 3 cases of B/Yamagata, respectively.
A HIV-Uninfected Cohort, Mothers B HIV-Uninfected Cohort, Infants

1.00 0.05 1.00 0.10
P=0.01 P=0.01
Placebo
with Confirmed Influenza

Proportion of Mothers
0.75 0.75
Proportion of Infants
0.03 0.05
Placebo
IIV3
0.50 0.50
IIV3
0.00 0.00
0.25 0 2 4 6 8 10 0.25 0 2 4 6
0.00 0.00
0 2 4 6 8 10 0 2 4 6
Months since Vaccination Age (mo)
No. at Risk No. at Risk
IIV3 1062 1047 1007 985 703 159 IIV3 1026 1004 981 897
Placebo 1054 1023 993 964 685 179 Placebo 1023 993 960 873
C HIV-Infected Cohort, Mothers D HIV-Infected Cohort, Infants

1.00 1.00 0.10
P=0.59
Placebo
P=0.03

Proportion of Mothers
0.75 0.75
Proportion of Infants
0.05 IIV3
0.50 0.50
0.00
0.25 0.25 0 2 4 6
Placebo
IIV3
0.00 0.00
0 2 4 6 8 10 0 2 4 6
Months since Vaccination Age (mo)
No. at Risk No. at Risk
IIV3 100 95 91 86 61 9 IIV3 100 93 86 68
Placebo 94 87 78 74 53 7 Placebo 88 81 75 66
Figure 1. Kaplan–Meier Estimates of Percentages of Confirmed Cases of Influenza According to Cohort and Study Group.
Confirmed influenza was defined as influenza diagnosed by means of reverse-transcriptase–polymerase-chain-reaction assay. The in-
sets show the same data on an expanded y axis. HIV denotes human immunodeficiency virus, and IIV3 trivalent inactivated influenza
vaccine.
rates between them and between these infants protocol analysis. Although 23% of the HIV-in-
and those in the Bangladeshi study, for whom fected and uninfected immunogenicity cohorts
exposure was probably more prolonged.16,39 An- were outside the protocol-defined windows for
other limitation of our study is the fact that the obtaining post-vaccination blood samples, the re-
evaluation of vaccine efficacy among HIV-infect- sults were similar to those included in the ex-
ed women was a secondary objective; neverthe- ploratory immunogenicity analysis with an ex-
less, its efficacy in these women was indicated panded window. An inadvertent occurrence in the
by the high attack rate in the placebo group. study was the difference in HIV disease charac-
However, the study lacked power to evaluate vac- teristics between the placebo group and the IIV3
cine efficacy among the infants of HIV-infected group, including the fact that placebo recipients
women, for whom the point estimate was simi- were more likely to be receiving highly active
lar to that for HIV-uninfected infants in the per- antiretroviral therapy. However, this factor would

have biased the results in the direction of a re- the Department of Science and Technology and National Re-
search Foundation in Vaccine-Preventable Diseases, and the
duced risk of influenza in the placebo group.7 In Respiratory and Meningeal Pathogens Research Unit of the
addition, in HIV-infected women, the lower HAI Medical Research Council.
titers among placebo recipients as compared with Dr. Madhi reports receiving lecture fees and fees for serving
on advisory boards from GlaxoSmithKline, Pfizer, and Sanofi
IIV3 recipients could have been due to differences Pasteur and grant support from Novartis, GlaxoSmithKline,
in HIV disease stage between the groups. Pfizer, Sanofi Pasteur, and MedImmune; and Dr. Weinberg
In conclusion, these data show that IIV3 vac- consulting fees from Merck and grant support from Merck,
MedImmune, Becton Dickinson, Roche, and GlaxoSmithKline;
cination in pregnant HIV-uninfected and HIV- and Dr. Violari fees for serving on a data and safety monitoring
infected African women was immunogenic and board from Janssen and grant support from Janssen, Aeras,
provided protection against confirmed influenza. Gilead, and the Drugs for Neglected Diseases Initiative. No
other potential conflict of interest relevant to this article was
The vaccination was also effective in HIV-unex- reported.
posed infants up until 24 weeks after birth. Disclosure forms provided by the authors are available with
The contents of this report are solely the responsibility of the the full text of this article at NEJM.org.
authors and do not necessarily represent the official views of We thank all the study participants; the staff of the Depart-
their institutions or organizations or of the study sponsors. ments of Obstetrics, Neonatology, and Paediatrics at Chris
Supported by grants from the Bill and Melinda Gates Foun- Hani–Baragwanath Academic Hospital, Soweto, South Africa,
dation (OPP1002747), the National Institutes of Health, Na- for their dedication to their patients, including our trial partici-
tional Center for Advancing Translational Sciences Colorado pants; the study midwives, nurses, laboratory staff, counselors,
Clinical and Translational Sciences Institute (UL1 TR000154, and data capturers; and Niteen Wairagkar, program officer act-
for REDCap), the South African Research Chairs Initiative of ing on behalf of the Bill and Melinda Gates Foundation.
Appendix
From the Medical Research Council, Respiratory and Meningeal Pathogens Research Unit (S.A.M., C.L.C., L.K., A.H., S.J., P.V.A., N.N.,
K.P.K., M.C.N.), the Department of Science and Technology–National Research Foundation, Vaccine-Preventable Diseases (S.A.M.,
C.L.C., L.K., A.H., S.J., P.V.A., N.N., M.C.N.), and the Perinatal HIV Research Unit (A.V.), University of the Witwatersrand, the Na-
tional Institute for Communicable Diseases, the National Health Laboratory Service, Centre for Vaccines and Immunology (S.A.M., F.T.,
M.V.), Johannesburg, and the Department of Medical Virology, University of Pretoria, Pretoria (M.V.) — all in South Africa; the School
of Medicine and Children’s Hospital, University of Colorado (A.W.), the Department of Pediatrics, Medicine and Pathology, University
of Colorado School of Medicine (E.A.F.S.), and the Center for Global Health, Department of Epidemiology, Colorado School of Public
Health (E.A.F.S.) — all in Aurora, Colorado; the Department of Medicine and Department of Global Health, University of Washington
(J.R.O.), and the Vaccine Access and Delivery Global Program, PATH (J.R.O., K.M.N.) — both in Seattle; and the Hubert Department
of Global Health, Rollins School of Public Health, and the Division of Infectious Diseases, School of Medicine, Emory University, At-
lanta (K.P.K.).
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160:1277-83. za A2 and B viruses. J Hyg (Lond) 1972;70: (http://www.nicd.ac.za/?page=seasonal_
24. Radin JM, Katz MA, Tempia S, et al. 767-77. influenza&id=72).
Influenza surveillance in 15 countries in 32. Black S, Nicolay U, Vesikari T, et al. Copyright © 2014 Massachusetts Medical Society.
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Madhi 2014 Influenza Vaccination of Pregnant Women and Protection of Their Infants

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Madhi 2014 Influenza Vaccination of Pregnant Women and Protection of Their Infants

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The n e w e ng l a n d j o u r na l of m e dic i n e

Influenza Vaccination of Pregnant Women

918 n engl j med 371;10 nejm.org September 4, 2014

The New England Journal of Medicine

n engl j med 371;10 nejm.org September 4, 2014 919

920 n engl j med 371;10 nejm.org September 4, 2014

The New England Journal of Medicine

n engl j med 371;10 nejm.org September 4, 2014 921

Characteristic or Outcome Overall IIV3 Placebo

922 n engl j med 371;10 nejm.org September 4, 2014

The New England Journal of Medicine

HIV-Infected Cohort fants of placebo recipients were A/H3N2 (14 in-

Vaccine Efficacy Safety

n engl j med 371;10 nejm.org September 4, 2014 923

Characteristic or Outcome Overall IIV3 Placebo

924 n engl j med 371;10 nejm.org September 4, 2014

The New England Journal of Medicine

Characteristic or Outcome Overall IIV3 Placebo

n engl j med 371;10 nejm.org September 4, 2014 925

926 n engl j med 371;10 nejm.org September 4, 2014

The New England Journal of Medicine

Measure A(H1N1)pdm09 A/H3N2 B/Victoria

IIV3 Placebo P Value† IIV3 Placebo P Value† IIV3 Placebo P Value†

The New England Journal of Medicine

n engl j med 371;10 nejm.org September 4, 2014

Copyright © 2014 Massachusetts Medical Society. All rights reserved.

Efficacy End Point HIV-Uninfected Cohort HIV-Infected Cohort

IIV3 Placebo Vaccine IIV3 Placebo Vaccine

The New England Journal of Medicine

(14.3 to 18.8) (14.9 to 19.6) (16.0 to 33.6) (19.9 to 39.0)

n engl j med 371;10 nejm.org September 4, 2014

Copyright © 2014 Massachusetts Medical Society. All rights reserved.

A HIV-Uninfected Cohort, Mothers B HIV-Uninfected Cohort, Infants

with Confirmed Influenza

C HIV-Infected Cohort, Mothers D HIV-Infected Cohort, Infants

with Confirmed Influenza

n engl j med 371;10 nejm.org September 4, 2014 929

930 n engl j med 371;10 nejm.org September 4, 2014

The New England Journal of Medicine

posting presentations from medical meetings online

n engl j med 371;10 nejm.org September 4, 2014 931

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