ReviewThe status of live viral vaccination 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
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Effect of measles vaccination in infants younger than 9 months on the immune response to subsequent measles vaccine doses: a systematic review and meta-analysis
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Importance of Virus Characteristics in Respiratory Syncytial Virus-Induced Disease
2019, Immunology and Allergy Clinics of North AmericaCitation Excerpt :The lower levels of interferons may allow RSV to spread more widely in the respiratory tract. Because interferons also serve to enhance the adaptive immune response,41–45 the ability of NS1 and NS2 to reduce the level of interferons during RSV infection likely contributes to the short-lived protective immunity. The adaptive immune response to RSV does not prevent periodic reinfection throughout life.
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2015, VaccineCitation Excerpt :However, there is some indication that premature vaccinations may cause a suboptimal vaccine protection due to interference by maternal antibodies. Recently, the immature immune system of infants was proposed as another possible explanation of a suboptimal protection; for example, independent of maternal measles antibodies, specific humoral immunity was suboptimal in children vaccinated under six months of age compared to older children [7,8]. The timing of vaccine administration between subsequent vaccine doses also seems to play an important role in determining an optimal vaccine response.
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