Viral Hemorrhagic Fevers in Pregnant Women and the Vaccine Landscape: Comparisons Between Yellow Fever, Ebola, and Lassa Fever
Purpose of Review
As research efforts have advanced to understand the pathophysiology of viral hemorrhagic fevers (VHF) and other epidemic viral infections and develop medical countermeasures such as vaccines, pregnant women have remained an underexamined subgroup. To better understand the implications of future outbreaks of VHF for pregnant women amidst an evolving vaccine landscape, we examine three pathogens—yellow fever, Ebola, and Lassa fever—each with different levels of evidence and understanding of disease in pregnancy and at varying stages of vaccine development.
There are very limited data available on yellow fever disease in pregnancy and the current live-attenuated 17D yellow fever vaccine is recommended for pregnant women at high risk of exposure. Evidence on Ebola virus disease in pregnancy shows very high case fatality rates (CFRs) among pregnant women and their infants, with mixed evidence on whether mortality is higher in pregnant women than non-pregnant adults. The replication-competent rVSV-ZEBOV vaccine is currently being offered to at-risk pregnant women in the Democratic Republic of the Congo after a revision to an earlier protocol that excluded them. For Lassa fever, there is evidence that CFR is higher in pregnant individuals than non-pregnant adults, especially later in gestation, with high rates of fetal or perinatal loss associated with infection. There are currently no Lassa fever vaccine candidates that have been tested in humans.
More evidence is needed to fully understand the implications of infection in pregnancy, but the existing data underscore the serious maternal and fetal health risks associated with each viral infection. It will also be critical to generate evidence on the safety profile of vaccine candidates as they advance through the pipeline to ensure timely and appropriate access for pregnant women at risk of infection. It is important that pregnant women be considered in the design and clinical trial phases of future vaccines.
KeywordsEbola Lassa fever Yellow fever Vaccines Pregnancy Maternal immunization
One of the authors [CBK] received support from the Wellcome Trust under grant 203160/Z/16/Z.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.World Health Organization (WHO). An R&D blueprint for action to prevent epidemic - plan of action May 2016. 2016.Google Scholar
- 3.World Health Organization (WHO). Guidance for managing ethical issues in infectious disease outbreaks. World Health Organization. 2016. Accessed August 1, 2018. Available from: http://www.who.int/ethics/publications/infectious-disease-outbreaks/en/.
- 4.Bloom DE, Black S, Rappuoli R. Emerging infectious diseases: a proactive approach. Proc Natl Acad Sci. 2017;7:201701410.Google Scholar
- 5.•• Gomes MF, de la Fuente-Núñez V, Saxena A, Kuesel AC. Protected to death: systematic exclusion of pregnant women from Ebola virus disease trials. Reprod Health. 2017;14:172. https://doi.org/10.1186/s12978-017-0430-2Provides an overview of the systematic exclusion of pregnant women from trials conducted during the West African Outbreak. CrossRefPubMedPubMedCentralGoogle Scholar
- 7.•• Krubiner CB, Faden RR, Karron RA, Little MO, Lyerly AD, Abramson JS, et al. Pregnant women & vaccines against emerging epidemic threats: ethics guidance for preparedness, research, and response. Vaccine. 2019. https://doi.org/10.1016/j.vaccine.2019.01.011 Available from: https://www.sciencedirect.com/science/article/pii/S0264410X19300453 Accessed 18 July 2019. Provides guidance of the ethical inclusion of pregnant women in epidemic vaccine research and deployment campaigns.
- 9.FIGO. Pregnancy and vaccination. April 24, 2019. Available from: https://www.figo.org/news/pregnancy-and-vaccination-0016175. Accessed 20 July 2019.
- 11.Røttingen JA, Gouglas D, Feinberg M, Plotkin S, Raghavan KV, Witty A, et al. New vaccines against epidemic infectious diseases. N Engl J Med. 2017.Google Scholar
- 17.Nigeria Centre for Disease Control (NCDC). Disease situation reports: an update of Lassa fever outbreak in Nigeria. 2019 Lassa fever outbreak situation report. 8 September 2019 Available from: https://ncdcgovng/themes/common/files/sitreps/2298ace1545cc7da74ce4d565bbfee77pdf Accessed 20 September 2019.
- 18.Nigeria Centre for Disease Control (NCDC). Disease situation reports: an update of yellow fever outbreak in Nigeria. Situation report of cluster of yellow fever outbreak in Bauchi State. 11 September 2019. Available from: https://ncdc.gov.ng/themes/common/files/sitreps/f722f4d1e81d6ad8f32cb00859c898d5.pdf Accessed 20 September 2019.
- 19.Nigeria Demographic and Health Survey. 2018. Key indicators report. Available from: https://dhsprogram.com/publications/publication-PR118-Preliminary-Reports-Key-Indicators-Reports.cfm. Accessed 20 September 2019.
- 20.Assaf S, Wang W. Regional disparities in fertility preferences and demand satisfied for family planning by modern methods across levels of poverty. DHS Analytical Studies No. 71. Rockville, Maryland, USA: ICF. August 2019. Available from: http://dhsprogram.com/pubs/pdf/AS71/AS71.pdf. Accessed 20 September 2019.
- 21.World Health Organization. Addressing sex and gender in epidemic-prone infectious diseases. 2007. Available from: https://apps.who.int/iris/bitstream/handle/10665/43644/9789241595346_eng.pdf Accessed 20 September 2019.
- 23.WHO Africa. Mothers survive Ebola while pregnant against the odds in the Democratic Republic of the Congo. 2 October 2019. Available from: https://www.afro.who.int/news/mothers-survive-ebola-while-pregnant-against-odds-democratic-republic-congo. Accessed 3 October 2019.
- 26.Schwartz DA. Clinical trials and administration of Zika virus vaccine in pregnant women: lessons (that should have been) learned from excluding immunization with the Ebola vaccine during pregnancy and lactation. Vaccines (Basel). 2018;6(4). https://doi.org/10.3390/vaccines6040081 Available from: https://www.mdpi.com/2076-393X/6/4/81/htm.CrossRefGoogle Scholar
- 27.Faden R, Karron R, Krubiner C. An ‘indefensible’ decision: not vaccinating pregnant and lactating women in an Ebola outbreak. STAT News, August 27, 2018. Available from: https://www.statnews.com/2018/08/27/ebola-vaccine-pregnant-lactating-women/ Accessed 1 July 2019.
- 28.Schwartz DA. Maternal and infant survival following Ebola infection –their exclusion from treatment and vaccine trials and “Primum non nocere”. In: Pregnant in the time of Ebola: women and their children in the 2013-2015 West African epidemic. D.A. Schwartz, J.A. Anoko, S. Abramowitz, eds. Springer Nature, New York and Berlin Pgs. 147-155. Website: https://link.springer.com/chapter/10.1007/978-3-319-97637-2_10, 2019
- 30.Ryan ET. Yellow fever. UpToDate. 2018. Available from: https://www.uptodate.com/contents/yellow-fever Accessed 17 July 2019.
- 31.Garske T, Van Kerkhove MD, Yactayo S, Ronveaux O, Lewis RF, Staples JE, et al. Yellow fever in Africa: estimating the burden of disease and impact of mass vaccination from outbreak and serological data. PLoS Med. 2014;11(5):e1001638 Available from: https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001638 Accessed 3 August 2019.PubMedPubMedCentralCrossRefGoogle Scholar
- 32.WHO. Yellow fever fact sheet. 2019. Available from: https://wwwwhoint/en/news-room/fact-sheets/detail/yellow-fever Accessed 16 July 2019.
- 34.WHO. Yellow fever – Brazil. 2018. Available from: https://www.who.int/csr/don/27-february-2018-yellow-fever-brazil/en/ Accessed 15 July 2019.
- 35.Ribeiro CF, Soares ACG, Lopes VGS, Brasil P, De Filippis AMB, Nunes PCG. Maternal and fetal death after dengue infection: insights on dengue diagnosis. J Infect Dis Epi. 2017;3(2). https://doi.org/10.23937/2474-3658/1510035 Available from: https://clinmedjournals.org/articles/jide/journal-of-infectious-diseases-and-epidemiology-jide-3-035.php?jid=jide Accessed 1 August 2019.
- 37.Schwartz DA. The origin and emergence of Zika virus, the newest TORCH infection - what’s old is new again. Arch Pathol Lab Med. 2017;141(1):18–25. https://doi.org/10.5858/arpa.2016-0429-ED Available from: https://www.archivesofpathology.org/doi/10.5858/arpa.2016-0429-ED Accessed 15 July 2019.CrossRefPubMedPubMedCentralGoogle Scholar
- 38.Marinho PS, Cunha AJ, Junior JA, Prata-Barbosa A. A review of selected arboviruses during pregnancy. Matern Health Neonatol Perinatol. 2017;3:17 Available from: https://mhnpjournal.biomedcentral.com/articles/10.1186/s40748-017-0054-0 Accessed 20 July 2019.PubMedPubMedCentralCrossRefGoogle Scholar
- 39.Bentlin MR, Almeida RA, Coelho KI, Ribeiro AF, Siciliano MM, Suzuki A, et al. Perinatal transmission of yellow fever, Brazil, 2009. Emerg Infect Dis. 2011;17(9):1779–80. https://doi.org/10.3201/eid1709110242 Available from: https://wwwnccdcgov/eid/article/17/9/11-0242_article Accessed 10 August 2019.CrossRefPubMedPubMedCentralGoogle Scholar
- 40.Frierson JG. The yellow fever vaccine: a history. Yale J Biol Med. 2010;83(2):77–85 Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2892770/ Accessed 3 August 2019.PubMedPubMedCentralGoogle Scholar
- 41.Collins ND, Barrett ADT. Live attenuated yellow fever 17D vaccine: a legacy vaccine still controlling outbreaks in modern day. Curr Infect Dis Rep. 2017;19(3):14. https://doi.org/10.1007/s11908-017-0566-9 Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008154/ Accessed 12 July 2019.CrossRefPubMedPubMedCentralGoogle Scholar
- 42.• Beck AS, Barrett ADT. Current status and future prospects of yellow fever vaccines. Expert Rev Vaccines. 2015;14(11):1479–92. https://doi.org/10.1586/14760584.2015.1083430 Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5563254/. Accessed 3 August 2019. Provides an update of new yellow fever vaccines in development. CrossRefPubMedPubMedCentralGoogle Scholar
- 43.Bassi MR, Larsen MA, Kongsgaard M, Rasmussen M, Buus S, Stryhn A, et al. Vaccination with replication deficient adenovectors encoding YF-17D antigens induces long-lasting protection from severe yellow fever virus infection in mice. PLoS Negl Trop Dis. 2016;10(2):e0004464. https://doi.org/10.1371/journal.pntd.0004464.CrossRefPubMedPubMedCentralGoogle Scholar
- 45.WHO. 2014. Safety of immunization during pregnancy. A review of the evidence. Available from: https://wwwwhoint/vaccine_safety/publications/safety_pregnancy_nov2014pdf Accessed 20 July 2019.
- 47.•• Schwartz DA, Anoko JN, Abramowitz S, editors. Pregnant in the time of Ebola: women and their children in the 2013–2015 West African Epidemic: Springer; 2019. –New York and Berlin. [ISBN-13: 978-3319976365] [ISBN-10: 3319976362]. Provides an anthology with several relevant chapters on various aspects of Ebola and pregnancy. Google Scholar
- 48.Schwartz DA. Maternal filovirus infection and death from Marburg and Ravn viruses: highly lethal to pregnant women and their fetuses similar to Ebola Virus. In: Okware SI, editor. Re-Emerging Filovirus Diseases: IntechOpen; 2019. https://doi.org/10.5772/intechopen88270. ISBN: 978-1-78985-550-0. Available from: https://wwwintechopencom/online-first/maternal-filovirus-infection-and-death-from-marburg-and-ravn-viruses-highly-lethal-to-pregnant-women Accessed 15 August 2019.
- 49.Callaghan WM, Creanga AC, Jamieson DJ. Pregnancy-related mortality resulting from influenza in the United States during the 2009–2010 pandemic. Obstet Gynecol. 2015;126(3):486–90. https://doi.org/10.1097/AOG.0000000000000996 Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4557717/ Accessed 8 August 2019.CrossRefPubMedPubMedCentralGoogle Scholar
- 51.•• Okogbenin S, Okoeguale J, Akpede G, Colubri A, Barnes KG, Mehta S, et al. Retrospective cohort study of Lassa fever in pregnancy, southern Nigeria. Emerg Infect Dis. 2019;25(8). https://doi.org/10.3201/eid2508.181299 Available from: https://wwwnc.cdc.gov/eid/article/25/8/18-1299_article Accessed 15 August 2019. Provides one of the few analyses of maternal and fetal outcome with Lassa fever infection. PubMedCentralCrossRefPubMedGoogle Scholar
- 54.Thomas RE, Lorenzetti DL, Spragins W, Jackson D, Williamson T. The safety of yellow fever vaccine 17D and 17DD in children, pregnant women, HIV+ individuals, and older persons: systematic review. Am J Trop Med Hyg. 2012;86(2):359–72. https://doi.org/10.4269/ajtmh.2012.11-0525 Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3269291/ Accessed 1 August 2019.CrossRefPubMedPubMedCentralGoogle Scholar
- 56.CDC. Ebola virus disease distribution map: cases of Ebola virus disease in africa since 1976. Updated 19 June 2019. Available from: https://www.cdc.gov/vhf/ebola/history/distribution-map.html. Accessed 2 October 2019.
- 57.WHO. Ebola virus disease - Democratic Republic of the Congo: external situation report 61. 1 October 2019. Available from: https://www.who.int/publications-detail/ebola-virus-disease-democratic-republic-of-congo-external-situation-report-61-2019. Accessed 2 October 2019.
- 61.Bebell LM. Ebola virus disease and pregnancy: perinatal transmission and epidemiology. In: Schwartz D, Anoko J, Abramowitz S, editors. Pregnant in the Time of Ebola. Global Maternal and Child Health (Medical, Anthropological, and Public Health Perspectives). Cham: Springer; 2019. p. 53–65.Google Scholar
- 64.Baggi FM, Taybi A, Kurth A, Van Herp M, Di Caro A, Wolfel R, Gunther S, Decroo T, Declerck H, Jonckheere S. Management of pregnant women infected with Ebola virus in a treatment centre in Guinea, June 2014.Google Scholar
- 66.Henwood PC, Bebell LM, Roshania R, Wolfman V, Mallow M, Kalyanpur A, et al. Ebola virus disease and pregnancy: a retrospective cohort study of patients managed at 5 Ebola treatment units in West Africa. Clin Infect Dis. 2017;65(2):292–9. https://doi.org/10.1093/cid/cix290.CrossRefPubMedPubMedCentralGoogle Scholar
- 67.Caluwaerts S, Van Herp M, Cuesta JG, Crestani R, Ronsse A, Lagrou D, et al. Pregnancy and Ebola: survival outcomes for pregnant women admitted to MSF Ebola treatment centres in the West Africa outbreak. [Meeting Abstract; not peer reviewed]. F1000Res. 2018;7:945. https://doi.org/10.7490/f1000research.1115707.1.CrossRefGoogle Scholar
- 70.WHO. Healthy baby born to mother who survived Ebola. 15 December 2018. Available from: https://www.who.int/csr/disease/ebola/survivors/healthy-baby-born-to-ebola-survivor/en/ Accessed 29 September 2019.
- 71.Gulland A. Meet Nubia: the only baby ever to have survived Ebola. The Telegraph. 1 June 2018. Available from: https://www.telegraph.co.uk/global-health/science-and-disease/meet-nubia-baby-ever-have-survived-ebola/. Accessed 29 September 2019.
- 75.WHO Strategic Advisory Group of Experts (SAGE) on Immunisation. Update with the development of Ebola vaccines and implications of emerging evidence to inform future policy recommendations – background paper for SAGE deliberations. October 2018. Available from: https://www.who.int/immunization/sage/meetings/2018/october/presentations_background_docs/en/ Accessed 3 October 2019.
- 78.Henao-Restrepo AM, Camacho A, Longini IM, Watson CH, Edmunds WJ, Egger M, et al. Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola Ca Suffit!). Lancet. 2017;389(10068):505–18.CrossRefGoogle Scholar
- 79.INRB, WHO. Preliminary results on the efficacy of rVSV-ZEBOV-GP Ebola vaccine using the ring vaccination strategy in the control of an Ebola outbreak in the Democratic Republic of the Congo: an example of integration of research into epidemic response. 12 April 2019. Available from: https://www.who.int/csr/resources/publications/ebola/ebola-ring-vaccination-results-12-april-2019.pdf Accessed 3 October 2019.
- 80.Merck. FDA Accepts Merck’s biologics license application (BLA) and grants priority review for V920, the company’s investigational vaccine for Ebola Zaire virus [press release] (2019 Sept 17) [cited 2019 Oct 5]. Available from: https://www.mrknewsroom.com/news-release/ebola/fda-accepts-mercks-biologics-license-application-bla-and-grants-priority-review-v
- 82.Samai M, Seward JF, Goldstein ST, Mahon BE, Lisk DR, Widdowson MA, et al. The Sierra Leone trial to introduce a vaccine against Ebola: an evaluation of rVSV∆ G-ZEBOV-GP vaccine tolerability and safety during the West Africa Ebola outbreak. J Infect Dis. 2018;217(suppl_1):S6–15.PubMedPubMedCentralCrossRefGoogle Scholar
- 85.Schopper D, Ravinetto R, Schwartz L, Kamaara E, Sheel S, Segelid MJ, et al. Research ethics governance in times of Ebola. Public Health Ethics. 2016. https://doi.org/10.1093/phe/phw039.
- 86.Edmunds J, Jarvis C. Benefits risk analysis of vaccination of pregnant women with rVSV-ZEBOV as part of expanded access programme. Presentation to WHO SAGE. October 2018. Available from: https://www.who.int/immunization/sage/meetings/2018/october/presentations_background_docs/en/index1.html.
- 87.WHO WER. Report of the Strategic Advisory Group of Experts (SAGE) on immunization. October 2018. Available from: https://apps.who.int/iris/bitstream/handle/10665/276544/WER9349.pdf?ua=1 Accessed 5 Oct 2019.
- 88.Amid SL. Ebola surge, experts don’t give nod to vaccine in pregnancy. CIDRAP News. 2018 Oct 26. Available from: http://www.cidrap.umn.edu/news-perspective/2018/10/amid-ebola-surge-experts-dont-give-nod-vaccine-pregnancy. Accessed 5 Oct 2019.
- 89.Personal Communication. 28 Jan 2019.Google Scholar
- 90.Branswell H. Ebola vaccine will be provided to women who are pregnant, marking reversal in policy. STAT News. 2019. Available from: https://www.statnews.com/2019/02/20/ebola-pregnancy-reversal/ Accessed 24 September 2019.
- 91.WHO SAGE. SAGE Interim recommendations on vaccination against Ebola virus disease (EVD). 2019. Available from: https://www.who.int/immunization/interim_ebola_recommendations_feb_2019.pdf Accessed 3 Oct 2019.
- 92.Bedford J, Gercama I, Bardosh K. Social science and behavioural data compilation – November 2018. Social science in humanitarian action. November 2018 Available from: https://reliefwebint/sites/reliefwebint/files/resources/SSHAP%20data%20compilation%20brief%20November%202018pdf. Accessed 17 July 2019.
- 93.Bedford J, et al. Social science and behavioural data compilation, DRC Ebola outbreak, November 2018–February 2019. Social science in humanitarian action. March 2019 Available from: https://wwwsocialscienceinactionorg/updates-dr-congo-ebola-outbreak-2019. Accessed 3 Oct 2019.
- 94.Higgins A. Pregnant women in DRC finally receive Ebola vaccine. Devex. 28 June 2019. Available from: https://www.devex.com/news/pregnant-women-in-drc-finally-receive-ebola-vaccine-95204. Accessed 3 Oct 2019.
- 95.Rasmussen SA, Jamieson DJ. Ebola vaccine for pregnant women: one step closer but still more to go. STAT News. 13 June 2019. Available from: www.statnews.com/2019/06/13/ebola-vaccine-pregnant-lactating-women-2. Accessed 3 Oct 2019.
- 96.Personal Communication, 2019 Oct 6.Google Scholar
- 97.Uganda Medical Research Council. Uganda starts Ebola Vaccine Trial among Healthcare and Frontline Workers in Mbarara. 5 Aug 2019. Available from: https://www.mrcuganda.org/content/uganda-starts-ebola-vaccine-trial-among-healthcare-and-frontline-workers-mbarara.
- 98.WHO. Second Ebola vaccine to complement “ring vaccination” given green light in DRC. 23 Sept 2019. Available from: https://www.who.int/news-room/detail/23-09-2019-second-ebola-vaccine-to-complement-ring-vaccination-given-green-light-in-drc Accessed 24 September 2019.
- 104.WHO (2019). Lassa Fever fact sheet. Available from: https://www.who.int/en/news-room/fact-sheets/detail/lassa-fever. Accessed 21 Sep 2019.
- 105.Nigerian CDC. 2019 Lassa fever outbreak situation report. Serial No 31 4 August 2019 Available from: https://ncdcgovng/themes/common/files/sitreps/dd05ce463fb792c9b2fc3850bfe9ad73pdf. Accessed 19 August 2019.
- 107.• Price ME, Fisher-Hoch SP, Craven RB, McCormick JB. A prospective study of maternal and fetal outcome in acute Lassa fever infection during pregnancy. BMJ. 1988;297(6648):584–7 Provides only prospective assessment of maternal and fetal outcomes with Lassa fever infection. PubMedPubMedCentralCrossRefGoogle Scholar
- 109.Dan-Nwafor C. on behalf of team at Nigeria Centre for Disease Control (NCDC). Personal communication. Email sent to: Carleigh B. Krubiner. 19 August 2019.Google Scholar
- 110.World Health Organization. WHO Target Product Profile for Lassa virus Vaccine. 2017. Available from: http://www.who.int/csr/research-and-development/list_of_pathogens/en/ Accessed 23 September 2019.
- 111.CEPI. Our Portfolio. Available from: https://cepi.net/research_dev/our-portfolio/ Accessed 23 September 2019.
- 113.Inovio. Inovio first to advance Lassa fever candidate vaccine into a clinical trial. 21 May 2019. Available from: http://ir.inovio.com/news-and-media/news/press-release-details/2019/Inovio-First-to-Advance-Lassa-Fever-Candidate-Vaccine-Into-a-Clinical-Trial/default.aspx Accessed 24 September 2019.
- 114.Karron R, Krubiner C, Faden R. As the world prepares to fight Lassa fever, the interests of pregnant women must be part of the planning. STAT. 15 January 2019. Available from: https://www.statnews.com/2019/01/15/lassa-fever-vaccine-pregnant-women Accessed 24 September 2019.