Elsevier

Vaccine

Volume 31, Issue 21, 17 May 2013, Pages 2531-2537
Vaccine

Review
The status of live viral vaccination in early life

https://doi.org/10.1016/j.vaccine.2012.09.043Get rights and content

Abstract

The need for neonatal vaccines is supported by the high disease burden during the first year of life particularly in the first month. Two-thirds of childhood deaths are attributable to infectious diseases of which viruses represent key pathogens. Many infectious diseases have the highest incidence, severity and mortality in the first months of life, and therefore early life vaccination would provide significant protection and life savings. For some childhood viral diseases successful vaccines exist, such as against measles, mumps, rubella, varicella, influenza poliovirus, and rotavirus, but their use in the first year particularly at birth is not yet practiced. Vaccines against other key pathogens continue to elude scientists such as against respiratory syncytial virus. The obstacles for early and neonatal vaccination are complex and include host factors, such as a developing immune system and the interference of passively acquired antibodies, as well vaccine-specific issues, such as optimal route of administration, titer and dosing requirements. Importantly, additional host and infrastructure barriers also present obstacles to neonatal vaccination in the developing world where morbidity and mortality rates are highest. This review will highlight the current live viral vaccines and their use in the first year of life, focusing on efficacy and entertaining the barriers that exist. It is important to understand the successes of current vaccines and use this knowledge to determine strategies that are successful in young infants and for the development of new vaccines for use in early life.

Highlights

► Review of current live viral vaccines used in infants. ► Review of obstacles to yearly life viral vaccination. ► Review of different routes of administration of viral vaccines.

Introduction

The high disease burden during the first year of life underscores the need for neonatal vaccination. Recent estimates show that over 3 million deaths occur during the first month of life and approximately 5.5 million within the first year. Two-thirds of childhood deaths are attributable to infectious diseases and thus are targets for prevention through immunization [1].

Respiratory and diarrheal diseases are the leading cause of childhood deaths followed by measles. Respiratory syncytial virus (RSV), parainfluenza virus and influenza virus are key respiratory viral pathogens [1]. Vaccines against RSV and parainfluenza elude scientists, and despite the existence of vaccines against influenza, use in young infants is not currently practiced. However new strategies are on the horizon and will be mentioned below.

In contrast, for viral diseases such as measles, mumps, rubella, varicella, polio, and rotavirus, vaccines are available for use in childhood [2]. These immunizations provide valuable protection and serve as examples for future vaccines.

Nonetheless obstacles remain that preclude effective vaccination in the very young when incidence and mortality are highest. Vaccine needs for developed countries are different than those in the developing world. The infrastructure demands in the developing world suggest that strategies which will significantly impact childhood health must include vaccines administered at birth. Often birth represents the only interaction with health providers until children are ill, and thus an important time for providing preventive health measures [3], [4]. This article will review the current live viral vaccines and will highlight the known barriers to effective infant vaccination.

Vaccines provide preventive protection, and thus need to be given prior to exposure. Many infectious diseases have the highest incidence, severity and mortality in the first months of life. Respiratory viruses account for a significant disease burden in the very young. Of these RSV is the most common cause of acute lower respiratory tract infection, accounting for approximately 3.4 million hospitalizations and 200,000 deaths annually [5], [6]. Rates in infants are estimated to be 2–3 times higher, peaking at 2–7 months of age. This is followed by influenza which results in approximately 1 million severe cases and 100,000 deaths annually [7]. Thus, the target age group for vaccination against these viruses is infants in the first weeks of life in order to establish protective immunity by the time exposure occurs. While vaccines for RSV are currently under investigation, their status will be reviewed, as well as potential efforts to immunize young infants against influenza using the current live viral vaccine.

Despite advances to childhood health from the current viral vaccines, their use has led to epidemiological shifts that warrant exploration. Examples include rotavirus vaccine which has substantially reduced efficacy in the developing world compared with high and middle income nations and measles vaccines where the use of the vaccine for decades has created a new group of susceptible individuals, infants between 6 and 12 months of age. Rotavirus is the most common cause of severe gastroenteritis in children, causing approximately 500,000 deaths annually among children aged <5 [8]. Severe dehydrating gastroenteritis caused by rotavirus occurs primarily among children aged 4–23 months [9], [10]. The current live viral vaccines have excellent efficacy against disease in developed countries resulting in 85–98% reductions in severe rotavirus disease [11], [12], [13], [14], [15], [16]. In contrast these same vaccines have significantly reduced efficacy in the developing nations of 39–77% [17], [18], [19], the reasons for which are not fully understood but will be entertained below.

During the nearly 5 decades of measles immunization, vaccine recommendations have been adjusted to meet emerging epidemiological shifts. Most recently outbreaks in the developed world have highlighted the susceptibility of infants <12 months, a shift which more closely approximates the disease burden in the developing world. Measles remains the leading cause of vaccine preventable childhood mortality globally with 164,000 deaths annually [20] and highest fatality rates occurring during the first year of life [21], [22], [23]. Recent epidemics in the United States have reported 21% of cases were in children <12 months who also represented 26% of measles hospitalizations [24]. This is a result of most mothers in the U.S. having vaccine-induced measles immunity which provides less measles antibody to their infants transplacentally. By six months these infants are susceptible to measles [25], [26], [27], [28], [29], a scenario which is paralleled in other developed countries who have long standing measles immunization programs [30], [31]. Therefore a renewed interest in an early primary measles dose has arisen in the developed world, which aligns with the desire in developing nations. Data from early measles immunization will be reviewed.

Mumps and rubella are not diseases affecting infants and thus consideration of an early life vaccine is not supported. Further, data suggest that mumps immunity provided by MMR may not persist unlike measles and rubella and therefore an earlier dose may not be warranted [32]. Varicella is infrequently seen in neonates, and while severity of disease is higher than in older age groups mortality is not [33]. For these reasons these vaccines have not been tested in young infants and will not be discussed further.

Live viral vaccines are among the most effective strategies for inducing lifelong immunity with as little as a single dose [34]. Currently 5 of the 16 vaccines used routinely are live viral vaccines providing protection against poliovirus, rotavirus, measles, mumps, rubella, varicella, and influenza [2]. Live viral vaccines have high efficacy rates resulting in 90–100% disease reduction since their introduction with the exception of rotavirus and influenza vaccines.

How viral vaccines induce lasting immunity is not fully understood. It is clear that a strong innate immune response must be initiated which promotes the expansion of both CD4+ and CD8+ T lymphocytes [35], [36], [37]. T cells are important for viral clearance as well as inducing and maintaining lasting memory. Antibodies also play a role in protection against viral infection and the presence of antigen-specific antibodies has become the marker of vaccine efficacy [34], mainly due to the ease of their detection.

Many studies have documented the persistence of antibody titers to viral vaccination for decades [34], but what factors contribute to lasting memory B cell immunity are unknown. Additionally, a discordance between B and T cell immunity induced by viral vaccines I seen, especially in the persistence of these responses [38]. T cell immunity lasts for long periods of time even in the absence of detectable antibody titers. In this context, humoral immunity is boosted upon revaccination [39], [40], suggesting that T cells serve to boost the amnestic humoral response. The issue of host susceptibility in this situation is important but has not been established in humans since direct challenge studies are lacking. However, data from animals [41], and from areas where diseases are endemic therefore providing natural infectious exposures [42], suggest that these individuals are protected from viral infection, at least severe or symptomatic disease.

It unclear what the best markers for viral vaccine efficacy are. Historically vaccine efficacy has been based on the identification of humoral immunity but recent data suggest that T cell immunity may be equally or more important. This is relevant when considering the immunogenicity of viral vaccines in infants who possess immunologic restrictions. It has become clear that the susceptibility to infection is difficult to determine using routine markers for live viral vaccine efficacy.

What is known is that many factors influence the acquisition of lasting vaccine immunity including host factors, such as age, and vaccine-specific issues, such as vaccine titer and route of administration.

Nature provides infants with passive immunity to infections through the transplacental transfer of IgG during pregnancy and IgA in breast milk. Despite the obvious benefits to the young child, the levels of antibodies wane over time and are often not protective at the time of disease exposure. Unfortunately these titers even if non-protective may pose obstacles to some viral vaccines. This interference has been clearly demonstrated with measles immunization administered subcutaneously [43], [44] and rotavirus vaccine administered orally [45]. In the presence of passive antibodies (PA) measles and rotavirus humoral immunity is diminished. However, at least for measles, T cell responses are preserved and serve to boost the humoral responses to antigen re-exposure. These boosted antibody responses are of high avidity suggesting an amnestic response likely to be quickly protective [46], [47].

Research evaluating PA interference of infant responses to measles favors the hypothesis that PA directly masks specific B cell determinants, thus preventing antigen binding and recognition by infant B cells [48], [49]. T cell immunity is spared because the binding of the PA to vaccine antigen results in antibody-antigen complexes which are processed by antigen presenting cells for T cell presentation [50]. This allows for adequate T cell but limited B cell immune responses after the first antigen exposure, and would allow for T cell priming of B cell responses to subsequent antigen exposures, as seen in vaccine studies [46], [51]. An alternative mechanism, recently proposed, suggests that PA inhibits B cell activation through a negative feedback path when measles-specific IgG-measles virus complex binds to the B cell through that Fc receptor FcγRIIB, a known negative feedback mechanism for B cell activation [52]. Which mechanism is responsible for the blunting effects of PA in humans is not known, and would be important to understand if vaccines that can overcome this obstacle are to be developed.

Section snippets

Measles, mumps, rubella, and varicella

Of the viral vaccines, immunization against measles, mumps, rubella and varicella is administered through the subcutaneous route. The first targeted antigen in the group was measles, which carries a high rate of mortality particularly in infants. Immunization in the developed countries is recommended at 12–15 months of age based on studies performed decades ago showing that infants in this age group lack PA and thus this interference avoided. Immunization of children 12 months or older will not

Conclusions

Live viral vaccines are one of the most effective public health measures. Nonetheless, decreased immunogenicity when administered in infancy has thrown doubt on their viability for protecting the very young. Despite the relatively limited immune responses, clinical benefit has been documented. Thus, we may need to adjust our expectations for early vaccination to one of preventing disease severity and mortality rather than producing sterilizing immunity. There are approaches to vaccination that

References (99)

  • H. Gans et al.

    Measles and mumps vaccination as a model to investigate the developing immune system: passive and active immunity during the first year of life

    Vaccine

    (2003)
  • R.D. Weeratna et al.

    Priming of immune responses to hepatitis B surface antigen in young mice immunized in the presence of maternally derived antibodies

    FEMS Immunol Med Microbiol

    (2001)
  • D. Kim et al.

    Insights into the regulatory mechanism controlling the inhibition of vaccine-induced seroconversion by maternal antibodies

    Blood

    (2011)
  • P.M. Ndumbe et al.

    Comparison of Edmonston-Zagreb, Connaught and Schwarz measles vaccines in Cameroonian infants aged 3–8 months

    Vaccine

    (1995)
  • O. Tidjani et al.

    Serological effects of Edmonston-Zagreb, Schwarz, and AIK-C measles vaccine strains given at ages 4–5 or 8–10 months

    Lancet

    (1989)
  • M. Ceyhan et al.

    Immunogenicity and efficacy of one dose measles-mumps-rubella (MMR) vaccine at twelve months of age as compared to monovalent measles vaccination at nine months followed by MMR revaccination at fifteen months of age

    Vaccine

    (2001)
  • M.L. Garly et al.

    Measles antibody responses after early two dose trials in Guinea-Bissau with Edmonston-Zagreb and Schwarz standard-titre measles vaccine: better antibody increase from booster dose of the Edmonston-Zagreb vaccine

    Vaccine

    (2001)
  • R.M. Wong-Chew et al.

    Immunogenicity of aerosol measles vaccine given as the primary measles immunization to nine-month-old Mexican children

    Vaccine

    (2006)
  • J.A. Bellanti et al.

    Immunologic studies of specific mucosal and systemic immune responses in Mexican school children after booster aerosol or subcutaneous immunization with measles vaccine

    Vaccine

    (2004)
  • J. Chan et al.

    Maternal antibodies to rotavirus: could they interfere with live rotavirus vaccines in developing countries?

    Vaccine

    (2011)
  • A.D. Steele et al.

    Co-administration study in South African infants of a live-attenuated oral human rotavirus vaccine (RIX4414) and poliovirus vaccines

    Vaccine

    (2010)
  • J. Rhorer et al.

    Efficacy of live attenuated influenza vaccine in children: a meta-analysis of nine randomized clinical trials

    Vaccine

    (2009)
  • E. Negri et al.

    Influenza vaccine in healthy children: a meta-analysis

    Vaccine

    (2005)
  • R.B. Belshe et al.

    Efficacy of vaccination with live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine against a variant (A/Sydney) not contained in the vaccine

    J Pediatr

    (2000)
  • WHO
  • MMWR

    Vaccine-preventable diseases, immunizations, and MMWR—1961–2011

    MMWR Morb Mortal Wkly Rep

    (2011)
  • R. Menzies et al.

    Vaccine preventable diseases and vaccination coverage in Aboriginal and Torres Strait Islander people, Australia 2003 to 2006

    Commun Dis Intell

    (2008)
  • J.R. Groothuis et al.

    Prevention of serious respiratory syncytial virus-related illness. I. Disease pathogenesis and early attempts at prevention

    Adv Ther

    (2011)
  • U.D. Parashar et al.

    Global mortality associated with rotavirus disease among children in 2004

    J Infect Dis

    (2009)
  • R.I. Glass et al.

    The epidemiology of rotavirus diarrhea in the United States: surveillance and estimates of disease burden

    J Infect Dis

    (1996)
  • P.E. Kilgore et al.

    Trends of diarrheal disease—associated mortality in US children, 1968 through 1991

    JAMA

    (1995)
  • MMWR

    Prevention of rotavirus gastroenteritis among infants and children recommendations of the advisory committee on immunization practices (ACIP)

    MMWR Recomm Rep

    (2009)
  • MMWR

    Rotavirus vaccines: an update

    MMWR Wkly Epidemiol Rec

    (2009)
  • MMWR

    Rotavirus surveillance-worldwide, 2009

    MMWR Morb Mortal Wkly Rep

    (2010)
  • G.M. Ruiz-Palacios et al.

    Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis

    N Engl J Med

    (2006)
  • J.E. Tate et al.

    Monitoring impact and effectiveness of rotavirus vaccination

    Expert Rev Vaccines

    (2011)
  • T. Vesikari et al.

    Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine

    N Engl J Med

    (2006)
  • S.A. Madhi et al.

    Effect of human rotavirus vaccine on severe diarrhea in African infants

    N Engl J Med

    (2010)
  • CDC

    Global measles mortality, 2000–2008

    MMWR

    (2009)
  • P. Aaby et al.

    Reduced childhood mortality after standard measles vaccination at 4–8 months compared with 9–11 months of age

    BMJ

    (1993)
  • CDC

    Progress in reducing global measles deaths, 1999–2004

    MMWR

    (2006)
  • J. Zarocostas

    Mortality from measles fell by 91% in Africa from 2000 to 2006

    BMJ

    (2007)
  • CDC

    Update: Measles—United States, January–July 2008

    MMWR

    (2008)
  • H. Gans et al.

    Deficiency of the humoral immune response to measles vaccine in infants immunized at age 6 months

    JAMA

    (1998)
  • Gans H, Yasukawa L, Alderson A, Rinki M, DeHovitz R, Maldonado Y, Beeler J, Audet S, Arvin AM. Humoral and...
  • Y.A. Maldonado et al.

    Early loss of passive measles antibody in infants of mothers with vaccine-induced immunity

    Pediatrics

    (1995)
  • L.E. Markowitz et al.

    Changing levels of measles antibody titers in women and children in the United States: impact on response to vaccination. Kaiser Permanente Measles Vaccine Trial Team

    Pediatrics

    (1996)
  • M.M. Carson et al.

    Measles vaccination of infants in a well-vaccinated population

    Pediatr Infect Dis J

    (1995)
  • G.H. Dayan et al.

    Mumps outbreaks in vaccinated populations: are available mumps vaccines effective enough to prevent outbreaks?

    Clin Infect Dis

    (2008)
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