Portal de Periódicos da CAPES

Immunogenicity and efficacy of influenza immunization during pregnancy: recent and ongoing studies

2012; Elsevier BV; Volume: 207; Issue: 3 Linguagem: Inglês

10.1016/j.ajog.2012.07.001

1097-6868

Richard A. Adegbola, Mirjana Nesin, Niteen Wairagkar,

Bacterial Infections and Vaccines

Pregnant women and young infants are at increased risk from influenza. The World Health Organization and public health guidelines from Australia, Canada, and the United States recommend immunizing pregnant women with trivalent inactivated influenza vaccine. However, there are multiple barriers to the uptake of this recommendation. Additionally, current vaccines are not licensed for infants <6 months of age. Immunizing pregnant women would provide protection to both mothers and infants. The Bill & Melinda Gates Foundation (BMGF) and the National Institute of Allergy and Infectious Diseases (NIAID) are trying to address some of the issues associated with maternal immunization, which could be an effective intervention in both high- and low-resource settings to combat the significant maternal and infant morbidity and mortality due to influenza. BMGF and NIAID efforts are complementary to each other, focusing on evaluating the immunogenicity, efficacy, and safety of influenza vaccines during pregnancy; and the potential effect of maternal immunization on outcomes in infants in low-resource populations. Pregnant women and young infants are at increased risk from influenza. The World Health Organization and public health guidelines from Australia, Canada, and the United States recommend immunizing pregnant women with trivalent inactivated influenza vaccine. However, there are multiple barriers to the uptake of this recommendation. Additionally, current vaccines are not licensed for infants <6 months of age. Immunizing pregnant women would provide protection to both mothers and infants. The Bill & Melinda Gates Foundation (BMGF) and the National Institute of Allergy and Infectious Diseases (NIAID) are trying to address some of the issues associated with maternal immunization, which could be an effective intervention in both high- and low-resource settings to combat the significant maternal and infant morbidity and mortality due to influenza. BMGF and NIAID efforts are complementary to each other, focusing on evaluating the immunogenicity, efficacy, and safety of influenza vaccines during pregnancy; and the potential effect of maternal immunization on outcomes in infants in low-resource populations. By 2015, the United Nations Millennium Development Goals 4 and 5 aim to reduce mortality of children aged <5 years, and to reduce maternal mortality.1World Heath OrganizationAccelerating progress towards the health-related Millennium Development Goals.http://www.who.int/topics/millennium development goals/MDG-NHPS brochure 2010.pdfGoogle Scholar Infectious diseases remain the most important cause of child morbidity and mortality worldwide, accounting for two thirds of the estimated 8.8 million deaths in children aged <5 years in 2008. Most of these deaths occur in low-resource countries and approximately 41% occur during the neonatal period. Sepsis, pneumonia, and tetanus currently account for over one quarter of all neonatal deaths. In 2008, all-cause global maternal mortality was 342,900 deaths, with significant inequities persisting in low-resource settings.2Hogan M.C. Foreman K.J. Naghavi M. et al.Maternal mortality for 181 countries, 1980-2008: a systematic analysis of progress towards Millennium Development Goal 5.Lancet. 2010; 375: 1609-1623Abstract Full Text Full Text PDF PubMed Scopus (1413) Google Scholar Maternal immunization could be an effective intervention in low-resource settings to combat the high infant and maternal morbidity and mortality. In these settings, although adolescent or adult vaccination programs are not routinely available, there are existing platforms for delivery of vaccines to pregnant women that take advantage of the fact that 85% of countries have integrated World Health Organization (WHO)'s focused antenatal care approach in reproductive health programs and overall antenatal care rate of 70%, although there will be regions with much lower coverage.3World Health OrganizationReproductive health strategy to accelerate progress towards the attainment of international development goals and targets.http://whqlibdoc.who.int/hq/2010/WHO_RHR_10.14_eng.pdfGoogle Scholar The Maternal and Neonatal Tetanus Elimination Program provides an example of a successful, cost-effective maternal immunization strategy and serves as a potential platform on which other prevention measures could be built.4Roper M.H. Vandelaer J.H. Gasse F.L. Maternal and neonatal tetanus.Lancet. 2007; 370: 1947-1959Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar The Bill & Melinda Gates Foundation (BMGF) commissioned a report in 2010, to review the data and potential for different vaccines used during pregnancy to decrease severe disease in mothers and their newborn children.5Neuzil K.M. Ortiz J. Englund J. White C.J. PATH maternal immunization landscape analysis Report commissioned by the Bill & Melinda Gates Foundation.http://globalhealth/sites/idd/pneumonia/Reports/Maternal%20Immunization/MaternalImmunizationFinalReport_2010_09_09.pdfDate: September 2010Google Scholar The report identified influenza vaccine as the most promising next candidate for a maternal immunization strategy: the inactivated trivalent influenza vaccine (TIV) has been administered to millions of pregnant women in developed countries without safety concerns; multiple studies have shown that pregnant women were at greater risk in the H1N1 pandemic; there are increasing data regarding the burden and circulation of influenza in the tropics; and there is evidence of the indirect protection of infants through maternal immunization. Maternal influenza immunization is a promising option for protecting infants since no influenza vaccine has yet been licensed for use in infants 60%, suggesting that maternal immunization could protect infants during the first 6 months of life. There was an indication that influenza is common in tropical areas and may occur year-round. To confirm these findings in other low-resource settings and with sufficiently powered studies to examine both human immunodeficiency virus (HIV)-infected and uninfected populations of pregnant women, the BMGF maternal immunization portfolio funded 3 additional studies in Nepal, Mali, and South Africa (Table 1). The long-term goal of this project is to evaluate the efficacy (or lack thereof) of a strategy of immunization of women during pregnancy to protect the woman and her young infant from influenza. These studies, when completed, will advance decisions on vaccine introduction in this population group with benefits to the unimmunized infant. These studies are blinded, randomized, controlled studies of seasonal influenza vaccine delivered in the second and third trimester of pregnancy recruiting several thousand mother-infant pairs per study, conducted over 2 influenza seasons with the primary end point of efficacy against laboratory-confirmed influenza (LCI) in infants. Secondary endpoints include efficacy against LCI in mothers. Additionally, the studies will provide data on the incidence of influenza-like illness and LCI among pregnant women from the third trimester until 6 months postpartum, and in their infants up to 6 months of age. The studies also closely look at safety, including adverse obstetric events/pregnancy outcomes. The Mali group is using an active control; other studies are placebo controlled. The South African group is independently assessing the burden and vaccine efficacy in HIV-infected and uninfected women and their infants. These studies are not powered to show an effect against severe disease, but will record these events. The results from these studies are expected in 2014.TABLE 1Bill & Melinda Gates Foundation–funded burden of disease and efficacy studies of trivalent influenza vaccine underway in diverse settingsParameterLocationSarlahi, NepalBamako, MaliSoweto, South AfricaTrial endpointSafety and efficacy in mothers and infantsSafety and efficacy in mothers and infantsSafety and efficacy in mothers and infants with and without HIV infection/exposureGeographyAsia, densely populated rural settingFrancophone West Africa, urban settingSouthern Africa, urban settingInfant mortality rate (deaths/1000 live births)4710244HIV seroprevalence among pregnant women<1%2.3%29%ClimateSubtropicalTropicalTemperateInfluenza seasonalityYear-round, with peaks in winter (Jan-March)UnknownSharply seasonal, starting in late MayHIV, human immunodeficiency virus.Adegbola. Recent and ongoing influenza immunogenicity and efficacy studies. Am J Obstet Gynecol 2012. Open table in a new tab HIV, human immunodeficiency virus. Adegbola. Recent and ongoing influenza immunogenicity and efficacy studies. Am J Obstet Gynecol 2012. Following the initiation of these studies, BMGF organized an international meeting of multidisciplinary global health experts in London in June 2011 to discuss next steps in a maternal immunization strategy in low-resource settings and to identify the remaining gaps with regard to implementing the strategy successfully. The discussions at the meeting included the scientific, programmatic, communication, logistic, funding, legal, and regulatory issues that need to be addressed to translate maternal influenza immunization policy into public health action. There was a consensus from the meeting that efforts toward maternal immunization can begin now, and that they should begin with activities to understand how such a strategy could synergize with other family health programs. Proceedings of the meeting will be published elsewhere. Following the recommendation for influenza vaccination during pregnancy, the rate of vaccination of pregnant women in the United States remained low for years. In 2008, NIAID was preparing to conduct a study of inactivated trivalent seasonal vaccine from multiple manufacturers in pregnant women to generate additional safety and immunogenicity data. The emergence of the 2009 H1N1 pandemic virus fast-tracked that effort (Table 2) . Even early in the pandemic, it became obvious that the disease was more severe in pregnant women5Neuzil K.M. Ortiz J. Englund J. White C.J. PATH maternal immunization landscape analysis Report commissioned by the Bill & Melinda Gates Foundation.http://globalhealth/sites/idd/pneumonia/Reports/Maternal%20Immunization/MaternalImmunizationFinalReport_2010_09_09.pdfDate: September 2010Google Scholar and young infants than in healthy adults. This prompted expedited testing of inactivated monovalent vaccines against H1N1 virus in these populations. Focused efforts were placed on establishing safety and immunogenicity.TABLE 2National Institute of Allergy and Infectious Diseases studies of influenza vaccines in pregnant and postpartum women and their infantsAbbreviated titleObjectivesProduct and doseDesign/populationsStatusResults/commentsSeasonal influenza vaccinesSeason 2008/09: inactivated TIVClinicalTrials.govIdentifier: NCT00905125Safety (in mothers and infants until delivery)Immunogenicity (mothers only at 28 d postvaccination)Fluzone FluarixSingle, recommended dose (0.5 mL IM)200 healthy pregnant women randomized 1:1Completed, manuscript in preparation46 women received Fluzone56 women received FluarixNo safety signal detectedLocal and systemic reactogenicity: mild-moderate, similar in both groupsNo SAE was related to vaccinesImmunogenicity: subjects reached protective levels similar between 2 groupsSeason 2010/11 TIVsClinicalTrials.govIdentifier: NCT01173211Safety for mothers until delivery and infants until 6 wk of lifeImmunogenicity:Mothers: d 28, d 180, and deliveryInfants: cord blood and 6 wk of lifeFluarixFluzoneAgrifluSingle, recommended dose (0.5 mL IM)240 subjects, 3 arms: 60 pregnant and 20 nonpregnant women per armCompleted, final study report pending232 subjects enrolled (139 pregnant and 44 nonpregnant subjects; 49 infants)All infants delivered49 infants enrolled in 6-wk follow-upNo safety signal detectedAll deliveries resulted in a live birthNo SAE was related to vaccinesImmunogenicity not available yetComparing safety and immunogenicity of LAIV to TIV in postpartum breast-feeding womenClinicalTrials.govIdentifier: NCT01181323Safety for mothers and infants for 28 d postvaccinationBreast milk and serum IgG and IgAFluzoneFlumistSingle recommended dose240 healthy breastfeeding women randomized 1:1Group 1: LAIV (IN)/placebo (IM)Group 2: placebo (IN)/TIV (IM)EnrollingNo safety signal detected thus farImmunogenicity not available yetH1N1 vaccinesUnadjuvanted, monovalent H1N1 vaccine administered at 2 dose levelsClinicalTrials.govIdentifier: NCT00963430Safety to mothers and infants until deliveryImmunogenicity in mothers and in cord blood25 µg or 49 µg of HA120 pregnant women randomized 1:1 to 2 doses of 25 µg or 2 doses of 49 µg administered 21 d apartCompleted and published11Jackson L.A. Patel S.M. Swamy G.K. et al.Immunogenicity of an inactivated monovalent 2009 H1N1 influenza vaccine in pregnant women.J Infect Dis. 2011; 204: 854-863Crossref PubMed Scopus (88) Google ScholarNo safety signal detectedNo SAE was related to vaccinesLocal reactogenicity was more common in 49 µg groupSystemic reactogenicity was not different between groups, or first and second vaccinationsOne dose containing 25 µg of HA elicited an antibody response typically associated with protection against flu infectionEfficient transplacental transfer of maternal antibodiesNovartis H1N1 vaccine administered at 2 dose levelsClinicalTrials.govIdentifier: NCT00992719Safety to mothers, infants, and nonpregnant controlsImmunogenicityUnadjuvanted monovalent 15 or 30 μg HA200 pregnant women randomized 1:1 to two 15 μg doses or two 30 μg doses 21 d apart100 nonpregnant women: 2 doses of 15 μg HA 21 d apartCompleted, manuscript in preparation94 women enrolledNo safety signal detectedImmunogenicity data not completely finishedDivision of AIDS: H1N1 vaccine in HIV-infected womenClinicalTrials.govIdentifier: NCT00992017Safety in mother until delivery and in infants until 6 mo of lifeImmunogenicity:Mothers: d 21, d 42, and deliveryInfants: cord blood, age 3 mo, and age 6 mo30 μg of HATwo doses of 30 μg 21 d apartCompletedNo safety signal was reportedNo immunogenicity data are reportedAgriflu; Novartis Vaccines and Diagnostics, Cambridge, MA. Fluarix; GlaxoSmithKline Vaccines, Brentford, Middlesex, UK. Flumist; MedImmune, Gaithersburg, MD. Fluzone; Sanofi Pasteur, Lyon, France.HA, hemagglutinin; HIV, human immunodeficiency virus; IM, intramuscularly; Ig, immunoglobulin; IN, intranasal; LAIV, live attenuated influenza vaccine; NIAID, National Institute of Allergy and Infectious Diseases; SAE, serious adverse events; TIV, trivalent seasonal influenza vaccine.Adegbola. Recent and ongoing influenza immunogenicity and efficacy studies. Am J Obstet Gynecol 2012. Open table in a new tab Agriflu; Novartis Vaccines and Diagnostics, Cambridge, MA. Fluarix; GlaxoSmithKline Vaccines, Brentford, Middlesex, UK. Flumist; MedImmune, Gaithersburg, MD. Fluzone; Sanofi Pasteur, Lyon, France. HA, hemagglutinin; HIV, human immunodeficiency virus; IM, intramuscularly; Ig, immunoglobulin; IN, intranasal; LAIV, live attenuated influenza vaccine; NIAID, National Institute of Allergy and Infectious Diseases; SAE, serious adverse events; TIV, trivalent seasonal influenza vaccine. Adegbola. Recent and ongoing influenza immunogenicity and efficacy studies. Am J Obstet Gynecol 2012. NIAID has previously sponsored studies of vaccines in, or intended for, pregnant women. Examples of these studies include a study of vaccine to prevent group B streptococcus colonization8Prevention of GBS colonization via immunity.http://www.ClincalTrials.govGoogle Scholar and a pertussis vaccine study in healthy pregnant women.9Pertussis vaccine in healthy pregnant women.http://www.ClinicalTrials.govGoogle Scholar However, studies of vaccines against H1N1 influenza overshadowed these in terms of the numbers of pregnant women enrolled and the expedient requirement for results. Both seasonal and pandemic H1N1 vaccines were tested in healthy pregnant women and one in HIV-infected women (Table 2), providing the needed pivotal data on safety and immunogenicity of these products. These trials expanded local expertise in enrolling pregnant women in clinical trials and facilitated trials of seasonal influenza vaccines in pregnant women. Current studies also include postpartum women and their infants, as well as a live vaccine administered postpartum (Table 2). Thus far, NIAID has sponsored 6 studies to address some of the unresolved issues related to maternal immunization against influenza in the United States and worldwide (Table 2). Most studies are sponsored by the Division of Microbiology and Infectious Diseases (DMID) within NIAID, and are performed at NIAID-funded Vaccine and Treatment Evaluation Units (VTEUs). The current network of VTEUs comprises 8 sites in the United States. Operational capabilities of these units provide a framework for the types of studies that DMID could conduct. In general, they would be US-based, multicenter, randomized, double-blinded clinical trials. Thus far, the VTEUs have enrolled only healthy pregnant and lactating women and their infants, and pregnant women were enrolled in the second and third trimester of uncomplicated pregnancies. Inactivated, unadjuvanted influenza vaccines were administered to pregnant women and live attenuated vaccine has been studied in postpartum women. Primary outcomes were safety and immunogenicity compared to healthy adults. Some studies included healthy nonpregnant controls. Most studies assessed safety and immunogenicity in infants. Due to relatively small sample sizes, there has not been adequate statistical power to address vaccine efficacy in preventing disease or altering its course in pregnant women and/or their infants. The results of completed studies and preliminary results of ongoing studies indicate the following in terms of safety and immunogenicity. With regard to safety, both local reactogenicity during 7 days postvaccination and systemic reactogenicity were evaluated. The majority of local adverse events (AEs) associated with the vaccine were mild or moderate. The rates of local reactogenicity were similar among products and similar to those of nonpregnant controls. If an increased dose of vaccine was studied, more AEs were detected. However, their severity or frequencies were not above expected in nonpregnant controls. The majority of systemic reactogenicity was mild to moderate in severity, and similar among products. The most prevalent AE was malaise, followed by headache and nausea. Infrequently, subjects experienced elevated temperature in the 7 days following vaccination. All of the serious AEs reported in women and their infants were considered unrelated to the vaccine, and no specific trend was seen in the types of serious AEs reported. Immunogenicity in women was measured at baseline and at 21 or 28 days postvaccination. In terms of the geometric mean titer of the hemagglutination inhibition assay, a hemagglutination inhibition assay titer of ≥40, and a 4-fold increase in titer to influenza B, H1N1, and H3N2, were similar among groups and similar to those of nonpregnant controls. Immune responses were not significantly affected by gestational age at the time of vaccination or prior receipt of seasonal influenza vaccines. In some studies, immunogenicity was assessed in cord blood samples. Efficient transplacental transfer of antibodies was also documented. Overall immune responses after 1 dose recommended for adults of seasonal or H1N1 influenza vaccines among pregnant women in their second or third trimester reached levels that are generally accepted as protective. (More details may be found at the ClinicalTrials.gov website using identifiers provided in Table 2.) Two limitations of these studies were recognized. First, although recommendations for influenza immunization of pregnant women include immunization during the first trimester, subjects were enrolled only during second and third trimesters. Epidemiological data regarding the safety of seasonal influenza vaccines during early pregnancy are already available.10World Health OrganizationInfluenza vaccines.Wkly Epidemiol Rec. 2005; 80: 279-287PubMed Google Scholar Second, all studies were conducted in United States and their results may not be generalizable. The studies sponsored by the BMGF (described above) should bridge this gap. While designing and implementing these studies, DMID recognized a need to develop consistent definitions and grading of AEs during pregnancy. To address this need, DMID sponsored 3 consultative conferences with subject matter experts. The tools developed as a result of these meetings will soon be available and useful for other studies enrolling pregnant women. For studies enrolling pregnant and lactating women and their infants, DMID developed the following strategies. Research should be hypothesis-driven and should help inform policy in gap areas; it should respond to public health emergencies, should provide information regarding the changing epidemiology, and should evaluate the safety of existing and new products. The studies should complement planned trials by the pharmaceutical industry. However, there is currently no plan to design large efficacy trials, or provide data to support licensure. The results of the BMGF- and DMID-sponsored studies will contribute to a better understanding of the safety, immunogenicity, and efficacy of commercially available influenza vaccines in pregnant women and their infants. However, challenges remain that may require future studies in the areas of the safety of adjuvanted vaccines; the duration of protective immunity in infants depending on the timing of maternal immunization and the duration of breast-feeding; the immunogenicity and safety of influenza immunization during pregnancies complicated by comorbidities such as asthma, obesity, hypertension, and diabetes; and the cellular components of immunity and their effects on neonates. Although the WHO's Strategic Advisory Group of Experts on Immunization and the CDC's Advisory Committee on Immunization Practices have recommended the use of influenza vaccines during pregnancy, the uptake has been limited globally due to the lack of data for prioritizing influenza as a target and maternal influenza vaccination as a strategy in low-income countries, annual readministration requirement due to strain variations and nonapplicability of prepregnancy vaccination programs, trivalent formulations for Northern and Southern hemispheres may not give optimal coverage in the tropics, licensed influenza vaccine packet inserts do not provide clear-cut recommendation for use in pregnancy and off-label use remains a problem in developing countries. Thus, maternal immunization is a strategy worth exploring for the prevention of influenza-related morbidity and mortality among pregnant women and young infants. In the developing world, the burden of illness and deaths due to infectious diseases in pregnancy and early infancy is significant and much higher than in developed countries. Although transplacental antibody transfer may be reduced in developing-country settings due to maternal infections, such as malaria and HIV, higher rates of placenta dysfunction, higher total maternal IgG concentrations, and a higher incidence of preterm birth, the overall effect of immunization should be favorable. The Maternal and Neonatal Tetanus Elimination Initiative has provided a proof of concept that vaccination of pregnant women can be effective, logistically feasible, and culturally acceptable in developing and resource-limited settings. As with any new health intervention, health system, communications, and advocacy need must be addressed. We hope that BMGF and NIAID studies will result in enabling an environment for implementation of maternal influenza immunization by addressing the issues outlined as above, which will significantly contribute to United Nations Millennium Development Goals.