Healio
Healio
March 01, 2011
38 min read
Save

Immunization: Promoting Awareness and Increasing Coverage for Pediatric Patients

Immunization: Promoting Awareness and Increasing Coverage for Pediatric Patients

Introduction

Pneumococcal Conjugate Vaccine: A Decade of Use and the Road Ahead

Meningococcal Immunization: Aiming at a Moving Target

Rotavirus Disease in the Post-Vaccine Era and Current Status of Vaccines

Introduction

The number of recommended pediatric immunizations is increasing as more effective vaccines become available. In addition, the epidemiology of many pediatric diseases is complex and dynamic, with multiple disease organism serotypes varying in terms of geography, time, and virulence. This places a burden on health care professionals to ensure that they have current and adequate knowledge of changing disease epidemiology and advancements in prevention practices.

Streptococcus pneumoniae, Neisseria meningitidis, and rotavirus are responsible for significant childhood morbidity and mortality worldwide. Starting in 2000, vaccines that are effective in children became available for these 3 organisms, with 2 vaccines receiving licensure as recently as 2010. What are the implications of variations in the composition of these vaccines? What is the disease burden they are expected to reduce? What are their effectiveness and safety profiles? Have immunization recommendations been affected by postmarketing surveillance data? Are the most affected age groups eligible for and receiving the vaccine? How important is it to follow recommended immunization schedules?

This monograph will address these questions, focusing on the importance of vaccinating against pneumococcal, meningococcal, and rotavirus disease. After reading this monograph, health care practitioners will have greater insight of these vaccines and the diseases they prevent and should be motivated to educate patients and parents to ensure that every eligible child in their practice receives the vaccines.

Pneumococcal Conjugate Vaccine: A Decade of Use and the Road Ahead

Sir William Osler, an eminent early researcher in the pneumococcus field and one of the founders of Johns Hopkins Hospital, termed pneumococcus “The Captain of the Men of Death” and “The Old Man’s Friend.” At the time, pneumococcal disease was recognized as a disease of the elderly. Pneumococcus is now known to be a significant cause of disease in children, especially in those aged < 2 years.

Pneumococcus, or Streptococcus pneumoniae, is a gram-positive encapsulated organism usually seen as a diplococcus. Pneumococcus is a unique human pathogen, and is a common asymptomatic colonizer of the human nasopharynx. This organism can be spread by the host to other susceptible persons; some episodes of colonization can lead to pneumococcal disease within the host. Invasive pneumococcal disease (IPD) is defined as the infection of normally sterile body fluid. Examples include meningitis, bloodstream infections, cellulitis in soft tissues, or osteomyelitis when bone is affected. In pediatric cases, IPD most frequently manifests as either bacteremia or pneumonia, which often is seen on x-ray as lobar instead of diffuse bilateral pneumonia.

Epidemiology of IPD

Globally, pneumonia is responsible for 90% of pneumococcal deaths in children aged < 5 years. Although meningitis is recognized as an important manifestation of pneumococcal disease, it is responsible for only 7% of pneumococcal deaths in that age group.1 Three percent of deaths were due to non-pneumonia, non-meningitis syndromes. The United States and other developed countries have ready access to health care which contrasts with the health care setting in many less developed nations around the world. Parents recognize symptoms of pneumonia and are able to seek care; therefore, it is unusual for a child to have life-threatening pneumonia before treatment is started in developed country settings. However, there are still severe cases of pneumonia in the United States every year caused by pneumococcus, particularly in children who are immunodeficient.

Before the introduction of the pneumococcal conjugate vaccine, the age distribution of IPD cases followed a U-shaped curve, where children younger than 2 years of age and adults older than 65 years of age are at highest risk of disease (Figure 1). Examination of individuals aged 19 years and younger revealed that the highest incidences of IPD occurred in children aged 6 to 11 months and 12 to 17 months.2

Figure 1

Click here for larger version of Figure 1.

Children are at the greatest risk of disease from ages 6 through 18 months. In 1998, before the advent of the conjugate vaccine, rates of IPD in children in the United States aged 6 to 11 months and 12 to 23 months were 227.8 and 184.2 per 100,000, respectively.3

IPD incidence is affected by underlying medical conditions; for example, pre-vaccine disease rates among children with HIV infection or with sickle cell disease were significantly higher than among children in the general US population in all age groups through age 7 years.4,5

In the pre-vaccine era, IPD incidence also varied by ethnic group. In all age groups, American Indian, Alaska Natives, and black children had higher rates of disease than white children in the United States.6-10 Fortunately, the pneumococcal conjugate vaccine has resulted in dramatic reductions in disease in those higher-risk populations. Although health disparities are not completely eliminated in American Indians and Alaska Natives, considerable improvement has occurred.

The Pneumococcus Polysaccharide Capsule

The pneumococcus organism is encased in a polysaccharide capsule, which is its primary virulence factor. The capsule protects the organism against phagocytosis by granulocytes and macrophages and impedes complement. However, type-specific antibodies can act in concert with a phagocytic cell to engulf the bacterium. Ironically, it is the capsule which elicits an immune response from the human host. The capsule alone, however, elicits only a T-cell independent, non-boostable response. The capsule served as the target for development of the currently available vaccines.

Variation in capsule composition forms the basis for categorizing pneumococci. There are more than 91 serotypes grouped into 46 numbered serogroups. Serotypes are differentiated by letters affixed to the serogroup number (eg, 19A). In general, there is no immunologic cross-reactivity between the serogroups, but there is some cross-reactivity and therefore cross-protection within serogroups.

Serotype distribution varies by geography, age, time, and syndrome, and only a small number of serogroups or serotypes account for the majority of invasive disease. Twenty-three serotypes are responsible for > 90% of pneumococcal disease in adolescents and adults, while 11 cause up to 80% of cases in infants and children.11,12 Globally, 10 (95% CI, 9-12) serotypes are responsible for approximately 70% of pneumococcal disease in children aged < 5 years, while in North America, 7 serotypes account for more than 80% of disease in this youngest age group.

Those 7 serotypes were targeted for vaccine development, and include 4, 6B, 9V, 14, 18C, 19F, and 23F. Vaccines must be prepared independently for each serotype, which are then combined in one syringe. To prepare the conjugate vaccines, the polysaccharide capsule is covalently bonded to a protein carrier. The infant’s immune system is exposed, therefore, to a more antigenic protein with the capsule, and the resulting immune response is to the polysaccharide component as well. This strategy avoids the limitations inherent in a polysaccharide-only vaccine.13 The conjugate vaccine is highly immunogenic in early infancy, which is not an attribute of polysaccharide vaccines. As opposed to the T-cell independent response to a polysaccharide, the conjugate vaccine elicits a T-cell dependent response characterized by immune memory. In addition, hyporesponsiveness observed with multiple doses of a polysaccharide-only vaccine is avoided. Importantly, long-term protection is conferred by the conjugate vaccine as a result of the booster effect allowed by immune memory. Part of the protection conferred by the conjugate vaccine is a reduction in the prevalence of nasopharyngeal carriage of vaccine serotypes. This is the biological basis for the observation of herd immunity following implementation of immunization programs.

Available Pneumococcal Vaccines

Three vaccines are currently licensed in the United States (Table 1). The 23-valent polysaccharide vaccine has been available since 1983; however, it is not used in children aged < 2 years because young children lack a mature enough immune system to adequately respond to unconjugated polysaccharide antigens. Therefore, the use of the polysaccharide vaccine is delayed until children are old enough to respond to the vaccine, and then it is only given to those > 2 years of age who have an increased risk of disease. The 7-valent conjugate vaccine, licensed in 2000, was replaced by a 13-valent product that was licensed in 2010. A 10-valent pneumococcal conjugate vaccine is used in Europe but is not licensed in the United States.

Table 1

Click here for larger version of Table 1.

The serotypes of PCV7 account for more than 50% of serious pneumococcal disease among young children globally. The 6 serotypes added to complete the 13-valent vaccine formulation include the 3 remaining serotypes in the top 10 IPD contributors (Figure 2). These 3 serotypes—1, 5, and 19A—contribute approximately 10%, 8%, and 3% of IPD cases, respectively. Accordingly, their inclusion in the vaccine marks a significant advancement. Although serotype 6A is also included in the 13-valent vaccine, it shows cross-reactivity with serotype 6B, which is included in both the 7- and 10-valent conjugate vaccines.

Figure 2

Click here for larger version of Figure 2.

Numerous clinical trials have investigated the conjugate vaccines, internationally and in special ethnic groups. In a meta-analysis of randomized controlled trials of the pneumococcal conjugate vaccine in more than 57,000 children younger than 2 years of age, vaccine efficacy in preventing IPD caused by vaccine serotypes was 80% (95% CI, 58%-90%).14 Response was less for preventing IPD from all serotypes, with an efficacy of 58% (95% CI, 29%-75%). Efficacy in special populations varied, ranging from 65.0% in South African children who were HIV-positive, to 97.4% in the Northern California Kaiser Permanente study. In addition to immunogenicity and prevention of IPD as primary endpoints, trials have evaluated other outcomes including pneumonia, otitis media, and nasopharyngeal pneumococcal carriage. An efficacy gradient was observed, as the vaccine was less efficacious against nasopharyngeal colonization and infections that are more mucosal, while maximum efficacy was achieved against IPD, the least mucosal infection. This suggests that more antibody is required to prevent a mucosal infection compared to a nonmucosal infection.

A South African study reported some protection against non-pneumococcal respiratory diseases as well, such as respiratory syncytial virus (RSV) or influenza. This observation suggests that pneumococcus acts in concert with some of these viruses when children harbor dual infections (Table 2).15 Therefore, children who were immunized with the pneumococcal conjugate vaccine also had reductions in respiratory illnesses that were clinically categorized as being of a viral etiology against which they were not immunized.

Table 2

Click here for larger version of Table 2.

A study in Gambia enrolled more than 17,000 children in a randomized, placebo-controlled, double-blind trial of a 9-valent vaccine, with outcomes that included pneumonia, invasive disease, and mortality.16 All-cause mortality was reduced significantly by 16% (95% CI, 2%- 38%) among the children who were vaccinated with the pneumococcal conjugate vaccine. In this high mortality area, that reduction translates to 7 children whose lives were saved for every 1,000 who were vaccinated.

Many studies evaluated the effect of vaccine on pneumococcal nasopharyngeal carriage, using different conjugate vaccine products in several countries that follow varied immunization schedules. All studies demonstrated protection against acquisition of vaccine serotypes in the nasopharynx, and most studies showed an increase in the carriage of non-vaccine type strains, referred to as “replacement carriage.”

The conjugate vaccine safety profile is quite notable. Prelicensure, tens of thousands of children were enrolled in efficacy studies, and post-licensure studies have involved >160,000 children. In the 9 years since the vaccine became available, more than 200 million doses have been distributed worldwide with no serious safety issues. The carrier protein has been used with other vaccines as well, providing more than 20 years of conjugate vaccine experience. In addition, there are abundant data on the concomitant use of the pneumococcal conjugate vaccine with a wide variety of other vaccines, and it may be given concomitantly with DTP, DTaP, OPV, IPV, Hib, MMR, hepatitis B, and varicella vaccines. Its local reactogenicity is similar to that of other vaccines.

Pneumococcal Vaccine Impact

After the vaccine was licensed in 2000, immunization coverage increased steadily from 40.8% for 3 or more doses in 2002 to 92.6% for 3 or more doses and 80.4% for 4 or more doses in children aged 19 to 35 months in 2009.17 Therefore, a high coverage rate was achieved for either 3 or 4 doses of vaccine in a relatively short time.

Since the introduction of the vaccine, IPD caused by vaccine serotypes has been virtually eliminated from the pediatric population, undergoing a 100% reduction in disease caused by vaccine serotypes from 1998-1999 through 2007 in children < 5 years of age (Figure 3).18 Moreover, a significant 76% reduction in IPD caused by all serotypes was observed in this age group. There was a small increase in the rate of disease from serotype 19A and some other non-vaccine serotypes. However, the magnitude of that increase is not significant in relation to the vaccine serotype rate reduction. For example, although serotype 19A underwent a 253% increase in number of cases, that represents a rate increase of only 8 cases per 100,000 children.

Figure 3

Click here for larger version of Figure 3.

A change in disease rate was also seen among unvaccinated adults. Disease caused by the 7 serotypes in the vaccine underwent dramatic rate changes among the elderly as well as the non-elderly adult age population, with case reductions ranging from 92% to 97% in 2009 for all age groups compared with the baseline year. In addition, a 39% reduction in disease from all pneumococcus serotypes occurred among adults aged > 65 years, with marginal changes in other age strata. Therefore, despite the fact that adults are not vaccinated, they are protected when children who are vaccinated are no longer transmitting the organism to their elderly contacts.

Since the vaccine was introduced, 280,000 cases of IPD have been prevented in both children and adults. In addition, in the first 9 years of vaccine availability, 19,000 IPD-associated deaths were prevented (CDC, unpublished data).18

Vaccine effects on pneumonia were also impressive. A study in 2004 showed that, in addition to reduction in admissions for pneumococcal pneumonia in children and adults through age 39 years, expected hospitalizations were reduced for all-cause pneumonia as well, although at a lesser magnitude than the pneumococcal-specific admission reductions.19 This represents approximately 41,000 pneumonia admissions averted nationally in children aged < 2 years during 2004. In a recent study of the Nationwide Inpatient Sample that includes data from 1,045 hospitals in 38 states, it was estimated that in 2006 there were 36,300 fewer pneumonia hospitalizations among children aged < 2 years than that which occurred in the pre-immunization years of 1997 through 1999.20 Hospitalization rate for all-cause pneumonia did not change significantly during the study years (1997-2006), however, in children aged 2 to 4 years.

A summary of the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey outpatient visit data for any pneumonia before and during the early vaccine period revealed that outpatient visits for pneumonia in children aged < 2 years were reduced after the vaccine was introduced, although a large confidence interval precluded achieving statistical significance.21 Using the pre-conjugate vaccine era as a baseline, relative risk of an outpatient visit for any pneumonia was 0.85 (95% CI, 0.43-1.68) in the transition period (2000-2001), and 0.69 (95% CI, 0.38-1.24) in 2002 to 2003. Rates of both hospitalizations and ambulatory visits for all-cause pneumonia in children aged < 2 years continued to decline, with a 52.4% (P < .001) and 57.6% (P < .001) decrease in hospitalizations for all-cause pneumonia and pneumococcal pneumonia, respectively, in 2004 compared with 1997 to 1999.22 Similarly, ambulatory visits for all-cause and pneumococcal pneumonia declined by 41.1% and 46.9%, respectively, during the same time interval.

Prevention: The Road Ahead

While current pneumococcal vaccines have significantly reduced the burden of pneumococcal disease, continuing efforts may reduce the burden even further. For example, as disease incidence from the vaccine serotypes is reduced, replacement disease is occurring as infection with other serotypes increases. Rates of pneumococcal disease following immunization remain low, as replacement typically occurs with less virulent serotypes. However, the increase in serotype 19A after introduction of the 7-valent vaccine is an important exception.23 In addition to its virulence, this serotype has been shown to be multi-drug resistant.24 In a study from 8 US children’s hospitals, IPD decreased from 2001 through 2004, followed by an increase from 2005 through 2008, which was largely due to serotype 19A.25 This serotype increased significantly as a proportion of total admissions from 2001 onward. Serotype 19A comprised almost one-half of the non-vaccine serotypes, and 30% of the isolates were multidrug resistant. In addition, CDC Active Bacterial Core surveillance (ABCs) data from 2007 include 427 IPD cases with known serotype; of these, 64% are included in the 13-valent vaccine, and 42% were caused by serotype 19A.26 One-third of disease in children aged < 5 years was caused by non-vaccine types. The 13-valent conjugate vaccine is expected to decrease disease rates caused by the 6 additional serotypes in the formulation, including serotype 19A, and further decrease IPD in children. Therefore, continuing surveillance of the contribution to disease by all serotypes, as well as those in the currently available vaccines, is essential. Although following immunization there is replacement with nonvaccine serotypes in the nasopharynx, these serotypes are not very invasive. If increases in nonvaccine serotype disease continue despite the 13-valent vaccine, the magnitude will most likely be insignificant. The feasibility of developing conjugate vaccines with more than 13 serotypes is also being considered.

While current pneumococcal vaccines have significantly reduced the burden of pneumococcal disease, continuing efforts may reduce the burden even further.

In countries where conjugate pneumococcal vaccine had not yet been introduced—for example, Israel, Spain, and South Korea—disease attributable to 19A has also increased.27-29 Therefore, serotype changes must be interpreted with caution, and must not be totally ascribed to use of the pneumococcal conjugate vaccine.

Co-infections can affect vaccine efficacy, and their prevention, when vaccines are available, should be a priority (eg, influenza). Strategies to avoid the effects of infections for which immunization is currently unavailable (eg, malaria, HIV) must also be developed. Modifiable risk-conferring conditions should be targeted, including malnutrition and smoke exposure. In underserved geographic areas, socioeconomic development that ensures accessible health care should be pursued.

Research is underway to develop a vaccine from a protein antigen that is common across all strains of pneumococcus, including, among others, pneumococcal surface antigen A (PsaA), pneumococcal surface protein A (PspA), and pneumolysin (Ply).30 Some candidates are in preclinical studies, and others have reached the stage of phase 1 clinical trials.31

Different dosing schedules may also be feasible. In the United States, 3 priming doses are given at ages 2, 4, and 6 months, followed by a booster dose at 12 to 15 months. Some countries, including the United Kingdom, prime with 2 doses at 6 and 14 weeks, followed by a booster dose in the second year of life. Subsequent to the vaccine’s introduction in the United Kingdom in 2006, case numbers declined, and current year data indicate there is almost no IPD due to vaccine serotypes in children aged < 2 years.32 Therefore, the 2+1 schedule in the United Kingdom has had a dramatic impact.

Australia follows a pneumococcal immunization schedule of primary doses at 2, 4, and 6 months, completing the immunization. Data from Australia also show a significant reduction in IPD cases caused by vaccine serotypes, with a 75% reduction in cases in children aged < 2 years from vaccine introduction in 2002 until 2006.33 Cases were reduced by 82% in children aged 2 to 14 years during that interval, with other age groups undergoing IPD rate reductions ranging from 32% to 46%.

Summary

The highest risk of pneumococcal disease occurs at the extremes of age, leading to serious illness including meningitis, cellulitis in soft tissues, or osteomyelitis. The polysaccharide capsule is the primary virulence factor, and is the basis for the current vaccines. Since the advent of the conjugate vaccine, disease caused by serotypes in the vaccine have been almost eliminated, accompanied by a small increase in disease rates from non-vaccine serotypes. There has also been a reduction in overall IPD (ie, IPD caused by any serotype). An impact on pneumonia in the pediatric population and in some adult age strata has been observed, which extends to cases with non-pneumococcal etiologies. For the future, investigations of novel common protein vaccines are underway, and the feasibility, from the global perspective, of reduced dose schedules is being evaluated.

The fact that the conjugate vaccine is not the only factor influencing pneumococcal disease epidemiology must be kept in mind. Antibiotic misuse and overuse, which puts pressure on pneumococci to develop resistance and then offers the opportunity for them to proliferate in the nasopharynx, is probably equally, if not more, important. Therefore, there must be a 2-pronged approach to avoid an increase in replacement disease, by introducing vaccines that are highly effective, and by ensuring judicious use of antimicrobials.

References

  1. O’Brien KL, Wolfson LJ, Watt JP, et al; Hib and Pneumococcal Global Burden of Disease Study Team. Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates. Lancet. 2009;374(9693):893-902.
  2. Centers for Disease Control and Prevention. ABCs Report: Streptococcus pneumoniae, 1997. http://www.cdc.gov/abcs/reports-findings/survreports/spneu97.html. Accessed March 10, 2011.
  3. Advisory Committee on Immunization Practices. Preventing pneumococcal disease among infants and young children. Recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2000;49(RR-9):1-35.
  4. Mao C, Harper M, McIntosh K, et al. Invasive pneumococcal infections in human immunodeficiency virus-infected children. J Infect Dis. 1996;173(4):870-876.
  5. Gill FM, Sleeper LA, Weiner SJ, et al. Clinical events in the first decade in a cohort of infants with sickle cell disease. Cooperative Study of Sickle Cell Disease. Blood. 1995;86(2):776-783.
  6. Flannery B, Schrag S, Bennett NM, et al; Active Bacterial Core Surveillance/Emerging Infections Program Network. Impact of childhood vaccination on racial disparities in invasive Streptococcus pneumoniae infections. JAMA. 2004;291(18):2197-2203.
  7. O’Brien KL, Shaw J, Weatherholtz R, et al. Epidemiology of invasive Streptococcus pneumoniae among Navajo children in the era before use of conjugate pneumococcal vaccines, 1989-1996. Am J Epidemiol. 2004;160(3):270-278.
  8. Davidson M, Parkinson AJ, Bulkow LR, Fitzgerald MA, Peters HV, Parks DJ. The epidemiology of invasive pneumococcal disease in Alaska, 1986-1990—ethnic differences and opportunities for prevention. J Infect Dis. 1994;170(2):368-376.
  9. Cortese MM, Wolff M, Almeido-Hill J, Reid R, Ketcham J, Santosham M. High incidence rates of invasive pneumococcal disease in the White Mountain Apache population. Arch Intern Med. 1992;152(11):2277-2282.
  10. Lacapa R, Bliss SJ, Larzelere-Hinton F, et al. Changing epidemiology of invasive pneumococcal disease among White Mountain Apache persons in the era of the pneumococcal conjugate vaccine. Clin Infect Dis. 2008;47(4):476-484.
  11. World Health Organization. Immunization, Vaccines, and Biologicals. Pneumococcal vaccines. www.who.int/vaccines/en/pneumococcus.shtml. Accessed March 10, 2011.
  12. Hausdorff WP, Bryant J, Paradiso PR, Siber GR. Which pneumococcal serogroups cause the most invasive disease: implications for conjugate vaccine formulation and use, part I. Clin Infect Dis. 2000;30(1):100-121.
  13. Granoff DM, Feavers IM, Borrow R. Meningococcal vaccines. In: Plotkin SA, Orenstein WA, eds. Vaccines. 4th ed. Philadelphia, PA: WB Saunders Company; 2004:959-988.
  14. Lucero MG, Dulalia VE, Nillos LT, et al. Pneumococcal conjugate vaccines for preventing vaccine-type invasive pneumococcal disease and x-ray defined pneumonia in children less than two years of age. Cochrane Database Syst Rev. 2009;4:CD004977.
  15. Madhi SA, Klugman KP; Vaccine Trialist Group. A role for Streptococcus pneumoniae in virus-associated pneumonia. Nat Med. 2004;10(8):811-813.
  16. Cutts FT, Zaman SM, Enwere G, et al. Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in The Gambia: randomised, double-blind, placebo-controlled trial. Lancet. 2005;365(9465):1139-1146.
  17. Centers for Disease Control and Prevention. US Vaccination Coverage Reported via NIS. http://www.cdc.gov/vaccines/stats-surv/nis/default.htm#nis. Accessed March 10, 2011.
  18. Pilishivili T, Lexau C, Farley MM, et al; Active Bacterial Core Surveillance/Emerging Infections Program Network. Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine. J Infect Dis. 2010;201(1):32-41.
  19. Grijalva CG, Nuorti JP, Arbogast PG, Martin SW, Edwards KM, Griffin MR. Decline in pneumonia admissions after routine childhood immunization with pneumococcal conjugate vaccine in the USA: a time-series analysis. Lancet. 2007;369(9568):1179-1186.
  20. Centers for Disease Control and Prevention. Pneumonia hospitalizations among young children before and after introduction of pneumococcal conjugate vaccine—United States, 1997-2006. MMWR Morb Mortal Wkly Rep. 2009;58(1):1-4.
  21. Grijalva CG, Poehling KA, Nuorti JP, et al. National impact of universal childhood immunization with pneumococcal conjugate vaccine on outpatient medical care visits in the United States. Pediatrics. 2006;118(3):865-873.
  22. Zhou F, Kyaw MH, Shefer A, Winston CA, Nuorti JP. Health care utilization for pneumonia in young children after routine pneumococcal conjugate vaccine use in the United States. Arch Pediatr Adolesc Med. 2007;161(12):1162-1168.
  23. Proceedings from the 4th Regional Pneumococcal Symposium. March 2-3, 2009. Johannesburg, South Africa. http://www.sabin.org/files/attachment/4th%20Regional%20Pneumococcal%20Symposium_Downloadable.pdf. Accessed March 10, 2011.
  24. Pichichero ME, Casey JR. Emergence of a multiresistant serotype 19A pneumococcal strain not included in the 7-valent conjugate vaccine as an otopathogen in children. JAMA. 2007;298(15):1772-1778.
  25. Kaplan SL, Barson WJ, Lin PL, et al. Serotype 19A is the most common serotype causing invasive pneumococcal infections in children. Pediatrics. 2010;125(3):429-436.
  26. Centers for Disease Control and Prevention. Invasive pneumococcal disease in young children before licensure of 13-valent pneumococcal conjugate vaccine—United States, 2007. MMWR Morb Mortal Wkly Rep. 2010;59(9):253-257.
  27. Choi EH, Kim SH, Eun BW, et al. Streptococcus pneumoniae serotype 19A in children, South Korea. Emerg Infect Dis. 2008;14(2):275-281.
  28. Dagan R, Givon-Lavi N, Leibovitz E, Greenberg D, Porat N. Introduction and proliferation of multidrug-resistant Streptococcus pneumoniae serotype 19A clones that cause acute otitis media in an unvaccinated population. J Infect Dis. 2009;199(6):776-785.
  29. Fenoll A, Granizo JJ, Aguilar L, et al. Temporal trends of invasive Streptococcus pneumoniae serotypes and antimicrobial resistance patterns in Spain from 1979 to 2007. J Clin Microbiol. 2009;47(4):1012-1020.
  30. Jedrzejas MJ. Pneumococcal virulence factors: structure and function. Microbiol Mol Biol Rev. 2001;65(2):187- 207.
  31. Special Report. Seventh International Symposium on Pneumococci and Pneumococcal Diseases; March 14-18, 2010; Tel Aviv, Israel. http://www2.kenes.com/isppd/Documents/Report.pdf. Accessed March 10, 2011.
  32. Kaye P, Malkani R, Martin S, et al. Invasive pneumococcal disease (IPD) in England and Wales after 7-valent conjugate vaccine (PCV7); potential impact of 10- and 13-valent vaccines. Poster presented at: 27th Annual Meeting of the European Society for Paediatric Infectious Disease; June 9-13, 2009; Brussels, Belgium.
  33. Roche PW, Krause V, Cook H, et al. Invasive pneumococcal disease in Australia, 2006. Commun Dis Intell. 2008;32(1):18-30.

Meningococcal Immunization: Aiming at a Moving Target

Neisseria meningitidis is a major cause of invasive bacterial disease globally. Annual cases are estimated at 1.2 million, and it causes approximately 135,000 deaths. Disease can occur in epidemics, as in the meningitis belt of sub-Saharan Africa. Disease can also occur in outbreaks, as have been experienced in the United States. However, meningococcal disease typically occurs as sporadic cases in the United States.

Meningococcus transmission is via respiratory droplets from nasopharyngeal carriers. Carriage rates vary by age and time, increasing from < 5% in infancy to as high as 25% in adolescents aged 19 years, and decreasing to < 10% in persons aged 50 years.1 Disease incidence and serogroup distribution are highly variable and dynamic. However, similar to pneumococcal disease, the highest incidence is in infants. Even with therapy, the case fatality rate is approximately 12%, and 11% to 19% of survivors suffer long-term sequelae. Therefore, although meningococcal disease in the United States is now relatively rare, it can be a devastating illness, and patients often suffer permanent consequences, which may include limb amputation.

Similar to the pneumococcus, the major virulence factor for N meningitidis is the polysaccharide capsule, which is also the target of most meningococcal vaccines.2 There are 12 serogroups, of which 5 are responsible for most invasive disease globally (Table 1).3 The epidemiology varies considerably by serogroup. For example, serogroup A no longer causes disease in the United States, while it continues to be a major cause of epidemics globally, particularly in Africa. One potential explanation for the disappearance of serogroup A is environmental factors. For example, in the meningitis belt, disease flourishes during the dry season. The moment the rainy season begins, the disease essentially disappears. In addition, in Saudi Arabia there was an epidemic in the late 1980s, and American Muslims going to the Hajj developed disease on the airplanes returning to the United States. This transmission shows that there are environmental factors in addition to genetics in describing disease susceptibility. Although it is highly unpredictable, the possibility that serogroup A could reemerge should not be ruled out. W-135 had never caused an epidemic; then there was a W-135 epidemic during the Hajj of 2000. After the Hajjis from the sub-Saharan Africa meningitis belt returned home there was a large serogroup W-135 epidemic in Burkina Faso in 2002.

Table 1

Click here for larger version of Table 1.

Serogroup B is responsible for much of the endemic disease in the United States and elsewhere, and is the predominant serogroup in infants. However, incidence of disease caused by serotype B has declined.4 Serogroup C is a leading cause of endemic disease in the United States, and is the main serogroup responsible for outbreaks in schools and communities. Disease caused by serogroup C reached an incidence of approximately 0.5/100,000, which was the highest incidence of the 3 most common US serotypes in the last 20 years, during a peak from the early to mid-1990s, after which rates decreased to less than 0.1 per 100,000 by 2004. Serogroup Y caused a very small proportion of disease in the late 1980s, but by the mid-1990s it emerged as a substantial cause of disease, which was also followed by a substantial decline in incidence. W-135 is relatively uncommon in the United States.

The CDC Active Bacterial Core surveillance (ABCs) program obtains data for cases of invasive meningococcal disease from 10 sites throughout the United States with a population base of more than 40 million persons. Results projected to predict national rates indicate that the highest incidence is in children aged < 1 year.5 An adolescent peak that emerged in the 1990s remains, albeit attenuated, and in older age groups incidence rates are relatively low until an increase occurs once again in the elderly.

Licensed Meningococcal Vaccines and Current ACIP Recommendations for Use

Three meningococcal vaccines are currently available in the United States (Table 2). The first was a polysaccharide vaccine (Menomune), licensed in 1981. Limitations of the polysaccharide vaccine preclude its use in young children, who have the highest rates of disease. The first conjugate vaccine, MCV4-DT (Menactra), uses diphtheria toxoid as the protein carrier. This vaccine was licensed in 2005 for persons aged 2 to 55 years. MCV4-CRM (Menveo), conjugated to Corynebacterium diphtheriae CRM197 protein, was licensed in 2010 for persons aged 11 to 55 years. The 3 tetravalent vaccines cover serotypes A, C, W-135, and Y. A vaccine for serotype B is not yet available in the United States.

Table 2

Click here for larger version of Table 2.

Meningococcal Immunization Recommendations

The Advisory Committee on Immunization Practices (ACIP) currently recommends routine immunization of all adolescents aged 11 to 18 years, with vaccination ideally occurring at 11 to 12 years of age.6 In addition, persons aged 2 to 55 years who are at increased risk of meningococcal disease should be immunized with the conjugate vaccine. Eligible risk groups include:

  • College students
  • Travelers to endemic areas
  • Persons with asplenia
  • Persons with complement deficiencies in the terminal pathway
  • Outbreak control
  • Military recruits
  • Laboratory personnel exposed to N meningitidis
  • HIV-infected persons

In June 2009, the ACIP modified recommendations for revaccination with meningococcal conjugate vaccine.7 They now recommend that high-risk persons who were vaccinated between the ages of 7 and 55 years be revaccinated 5 years after the previous meningococcal vaccine. Previously vaccinated high-risk children aged 2 to 6 years should be revaccinated 3 years after their previous immunization. If the risk factor is ongoing, these groups should continue to be revaccinated at 5 year intervals.

In October 2010, expanded immunization recommendations for adolescents were also approved.8 Persons immunized at age 11 to 12 years should now receive a booster dose at age 16 years. Like all reimmunization recommendations, these new recommendations are based on antibody persistence data following immunization.

Since the introduction of the MCV4-DT conjugate vaccine in 2005, coverage rates for adolescents aged 11 through 18 years have increased steadily. However, coverage is still low. By 2009, approximately one-half of adolescents aged 13 to 17 years were immunized with a dose of MCV4-DT (Figure 1).

Figure 1

Click here for larger version of Figure 1.

Meningococcal Vaccine Impact

Preliminary data on the effectiveness of the MCV4-DT vaccine are emerging.9-11ABCs data show a selective disease reduction in the target ages of 11 through 19 years, and CDC estimates through reports of vaccine failures suggest effectiveness between 80% and 85% for serogroups C and Y.9 Early results from an ongoing case control study of MCV4-DT effectiveness, controlled for underlying illness and smoking, suggest an overall effectiveness of 78% (95% CI, 29%-93%) against serotypes C and Y, with 77% (95% CI, 14%-94%) against serotype C and 88% (95% CI, -23%-99%) against serotype Y.10 The large confidence intervals reflect the current low sample size of 107 cases enrolled; it is expected that acquiring additional data will increase the power of the study to more clearly define vaccine effectiveness.

The effectiveness study is also investigating duration of protection with MCV4-DT. Expectations were that the conjugate vaccine would elicit sustained protection. However, preliminary data suggest that vaccine effectiveness has waned over time in adolescents (Table 3). Data from the subgroup of subjects without underlying conditions showed similar decreases in effectiveness with time.

Table 3

Click here for larger version of Table 3.

The incidence and serogroup distribution of meningococcal disease in the United States fluctuate over time. After the peak in the mid-1990s dropped to the current nadir, a subsequent increase in cases was expected. However, the duration of the current low case level is impressive. Data from the Maryland ABCs site indicate that during increases in meningococcal diseases, the generation of novel antigenic variants occurs to which the population is not immune.12 In the current situation, it remains unknown if there will be a generation of new variants in the nasopharynx followed by a disease rate increase, or if the current low incidence represents a permanent change in the epidemiology of this disease.

In the United States, there has been limited ability to examine whether the vaccine has an impact on carriage, in part because carriage rates are currently very low.13 In the United Kingdom, a serogroup C conjugate vaccine is in use, and there has been a two-thirds to three-fourths reduction in nasopharyngeal carriage of serogroup C, which has resulted in a substantial herd effect.14,15

Both polysaccharide protein conjugate vaccines are very safe. Compared with the polysaccharide vaccines, they are more immunogenic, as would be expected with a conjugate vaccine.

Meningococcal Vaccines in the Pipeline

Successful conjugate vaccines for encapsulated bacteria that affect children with high rates of disease are available; for example, introduction of the Haemophilus influenzae type b (Hib) vaccine and the Streptococcus pneumoniae conjugate vaccines were followed by dramatic decreases in the associated diseases. In fact, disease caused by Hib has been virtually eliminated.

Extensive efforts are underway to develop a universal vaccine that is effective against serogroup B disease.

MCV4-DT is currently licensed for persons aged 2 to 55 years; it is anticipated that it will be approved as a 2-dose schedule to be given at ages 9 and 12 months. This indication expansion will continue to leave younger infants unprotected, however. An important next step is the introduction of meningococcal conjugate vaccines for infants, who have the highest rates of disease. A combination Hib meningococcal conjugate vaccine (HibMenCY-TT) is immunogenic when given following the typical pediatric schedule comprising vaccinations at ages 2, 4, 6, and 12 months, and is expected to be licensed in the future. MCV4-CRM, recently licensed for persons aged 11 through 55 years, has been shown to be highly immunogenic in infants as well using the typical schedule, and licensure for infants is anticipated.16

As with pneumococcal disease, there is a clear rationale for developing universal, serogroup-independent vaccines. There is no licensed serogroup B vaccine in the United States; therefore, extensive efforts are underway to develop a universal vaccine that is effective against serogroup B disease.

ACIP Decision on Immunization in Infants

As the time approaches when N meningitidis vaccines will become available for infants, it is important to know the ACIP perspective on universal immunization of infants with these vaccines. In their October 2009 workshop, the workgroup believed the ACIP should consider not adding meningococcal conjugate vaccine to the routine infant schedule.17 The predominant rationale for this decision was the low burden of disease at the present time. In addition, a large proportion of disease in infants is caused by serogroup B, for which there is no vaccine available. According to ABCs data, only 41% of disease in children younger than 1 year is potentially preventable with the currently available vaccines (CDC, Emerging Infections Program Network, unpublished data).18 The ACIP has made it clear that if the epidemiology changes, they will reconsider this recommendation.

The ACIP decision was also influenced by the low case-fatality ratio, which is lower among infants than it is among adolescents.17 If the 4-dose series in infants were introduced, an estimated 84 cases and 5 deaths per year would be prevented. Finally, other justifications for the decision include difficult programmatic aspects, the need to attain high coverage rates early, the potential for rare adverse events, and the undetermined need for a booster.

Summary

Meningococcal epidemiology is highly dynamic. The first conjugate vaccine to be licensed, MCV4-DT, is recommended for all adolescents aged 11 to 18 years and for specific high risk groups. Based on preliminary estimates since its introduction in 2005, MCV4-DT is effective. However, vaccine coverage remains suboptimal. A second conjugate vaccine, MCV4-CRM, was introduced in 2010 and can be used interchangeably with MCV4-DT in the age groups for which it is licensed. A variety of infant vaccines are expected to become available in the near future. However, based on current epidemiology and lack of a serogroup B vaccine, the ACIP currently will not recommend routine immunization of infants.

References

  1. Christensen H, May M, Bowen L, Hickman M, Trotter CL. Meningococcal carriage by age: a systematic review and meta-analysis. Lancet Infect Dis. 2010;10(12):853-861.
  2. Rosenstein NE, Perkins BA, Stephens DS, Popovic T, Hughes JM. Meningococcal disease. N Engl J Med. 2001;344(18):1378-1388.
  3. Granoff DM, Harrison LH, Borrow R. Meningococcal vaccines. In: Plotkin SA, Orenstein WA, Offit PA, eds. Vaccines. 5th ed. Philadelphia, PA: WB Saunders; 2008:399-434.
  4. Cohn AC, MacNeil JR, Harrison LH, et al. Changes in Neisseria meningitidis disease epidemiology in the United States, 1998-2007: implications for prevention of meningococcal disease. Clin Infect Dis. 2010;50(2):184-191.
  5. MacNeil J. Epidemiology of meningococcal disease in infants and young children. Presented at: Meeting of the Advisory Committee on Immunization Practices; October 21, 2009; Atlanta, GA.
  6. Bilukha OO, Rosenstein N; National Center for Infectious Diseases, Centers for Disease Control and Prevention (CDC). Prevention and control of meningococcal disease. MMWR Recomm Rep. 2005;54(RR-7):1-21.
  7. Centers for Disease Control and Prevention. Updated recommendation from the Advisory Committee on Immunization Practices (ACIP) for revaccination of persons at prolonged increased risk for meningococcal disease. MMWR Morb Mortal Wkly Rep. 2009;58(37):1042-1043.
  8. Meissner C, Chair. Harmonized Schedule Workgroup 2010. 2011 immunization schedules for children 0 through 18 years of age. Presented at: Meeting of the Advisory Committee on Immunization Practices; October 28, 2010; Atlanta,GA. http://www.cdc.gov/vaccines/recs/acip/downloads/mtg-slides-oct10/10-1-ChildSchedule.pdf. Accessed March 10,2011.
  9. Macneil JR, Cohn AC, Zell ER, et al; for the Active Bacterial Core surveillance (ABCs) Team and MeningNet Surveillance Partners. Early estimate of the effectiveness of quadrivalent meningococcal conjugate vaccine [published online ahead of print January 4, 2011]. Pediatr Infect Dis J. 2011. http://www.ncbi.nlm.nih.gov/pubmed/21206392. Accessed February 21, 2011.
  10. Cohn A. Optimizing the adolescent meningococcal vaccination program. Presented at: Advisory Committee on Immunization Practices Meeting; October 27, 2010; Atlanta, GA. http://www.cdc.gov/vaccines/recs/acip/downloads/mtg-slides-oct10/02-5-mening-mcv4.pdf. Accessed March 10, 2011.
  11. MacNeil J, Cohn AC, Mair R, Zell ER, Clark TA, Messonnier NE, MeningNet Partners Active Bacterial Core surveillance (ABCs) Team. Interim analysis of the effectiveness of quadrivalent meningococcal conjugate vaccine (MenACWY-D): a matched case-control study. Presented at: 17th International Pathogenic Neisseria Conference; September 13, 2010; Banff, Canada.
  12. Harrison LH, Jolley KA, Shutt KA, et al; Maryland Emerging Infections Program. Antigenic shift and increased incidence of meningococcal disease. J Infect Dis. 2006;193(9):1266-1274.
  13. Clark TA, Stern EJ, Pondo T, et al. The effect of quadrivalent (A, C, Y, W-135) meningococcal conjugate vaccine on serogroup-specific carriage of Neisseria meningitidis. Presented at: 16th International Pathogenic Neisseria Conference; September 7-12, 2008; Rotterdam, Netherlands. Abstract O52.
  14. Bettinger JA, Scheifele DW, Le Saux N, Halperin SA, Vaudry W, Tsang R; Canadian Immunization Monitoring Program, Active (IMPACT). The impact of childhood meningococcal serogroup C conjugate vaccine programs in Canada. Pediatr Infect Dis J. 2009;28(3):220-224.
  15. Kinlin LM, Jamieson F, Brown EM, et al. Rapid identification of herd effects with the introduction of serogroup C meningococcal conjugate vaccine in Ontario, Canada, 2000-2006. Vaccine. 2009;27(11):1735-1740.
  16. Snape MD, Perrett KP, Ford KJ, et al. Immunogenicity of a tetravalent meningococcal glycoconjugate vaccine in infants: a randomized controlled trial. JAMA. 2008;299(2):173-184.
  17. Cohn A. Considerations for use of meningococcal conjugate vaccines in infants. Presented at: Advisory Committee on Immunization Practices Summary Report. October 21-22, 2009; Atlanta, GA. http://www.cdc.gov/vaccines/recs/acip/downloads/min-oct09.pdf. Accessed March 10, 2011.
  18. Centers for Disease Control and Prevention. Active Bacterial Core Surveillance Reports: Neisseria meningitidis, 1999-2005. http://www.cdc.gov/abcs/reports-findings/surv-reports.html. Accessed March 10, 2011.

Rotavirus Disease in the Post-Vaccine Era and Current Status of Vaccines

In the United States, deaths from diarrhea are rare. However, it is the second leading cause of childhood death worldwide (Figure 1).1 Rotavirus is the leading cause of diarrhea globally and in the United States.2 The proportions of enteric disease caused by rotavirus in developing and developed countries, including the United States, are almost identical. Globally, more than 2 million hospitalizations, or approximately 40% of diarrheal hospitalizations in young children, are caused by rotavirus disease.3-5

Figure 1

Click here for larger version of Figure 1.

By the age of 5 years, almost every child has experienced an infection with rotavirus, and re-infection is common. According to a global analysis of studies published from 1986 to 2000, 111 million of these infections are treated with home care.4 Approximately 1 in 5 (25 million) patients make outpatient visits, 1 in 85 (2 million) are hospitalized, and 1 in 293 (440,000) die each year from the disease. The majority of these deaths occur in developing countries, with most in Africa and South Asia, particularly India.

Clinical Features of Rotavirus

The clinical features of rotavirus infections in the young child are very similar to those of any viral diarrhea.6 Profuse, watery diarrhea occurs in 5 to 20 episodes per day for a period of 5 to 9 days. Projectile vomiting is common. Fever has been documented in 30% to 50% of cases. Rotavirus diarrhea is the most common cause of dehydration and is more severe compared with bacterial diarrheas, with the exception of cholera. Irritability, lack of appetite, lethargy, and malaise accompany the infection.

Rotavirus is highly contagious, and is a very difficult organism to control, especially with regard to hospital-acquired infections.7,8 Common preventive measures for nosocomial infections, such as wearing gloves and gowns, are inadequate. The organism is resilient, and can survive on hands for hours, and on solid surfaces for days. Toys and even bed sheets are potential sources of infection. Rotavirus is stable in stools, and remains infective for a week.

Treatment of rotavirus diarrhea is the same as for any diarrhea. Rehydration is essential, especially for infants. After years of having only intravenous fluids available, powdered oral rehydration solutions are commercially available worldwide. In the United States, they are sold as pre-mixed solutions.

Rotavirus Structure

Rotaviruses have 3 distinct shell-like layers: a core, an inner capsid, and an outer capsid.9 The inner capsid of the rotavirus contains the major core protein VP6, which is the typical analyte in diagnostic ELISA tests. The outer capsid contains 2 surface proteins, the VP7 glycoprotein (G antigen), and the protease-cleaved VP4 spike protein (P antigen).10 Both P and G surface proteins are targets for neutralizing antibodies, and are believed to play a role in developing immunity against natural rotavirus.9,11

There are more than 40 G and P serotypes that have been documented in humans.12,13 The most common serotype is G1, which is found worldwide. G1, G2, G3, and G4 are responsible for almost 90% of rotavirus disease. There are, however, several emerging serotypes. G9 is establishing a global presence, while G8, G10, and G12 are increasing in specific locations around the world.14

Rotavirus Vaccines

The first rotavirus vaccine (Rotashield) to receive approval in the United States was a reassortant vaccine that contained 3 simian-human reassortant viruses and 1 simian rotavirus. This vaccine was withdrawn 9 months after its approval in 1998 due to its association with intussusception in immunized children, most of which occurred after the first vaccine dose.15

Two additional rotavirus vaccines have been extensively tested and are currently available. RV5 (RotaTeq), approved in 2006, is also a reassortant vaccine, derived from bovine rotavirus with a single human rotavirus gene substitution. RV5 is pentavalent, and contains the G1, G2, G3, G4, and P8 antigens. RV1 (Rotarix), approved in 2008, is a monovalent (G1P[8]) human vaccine that depends on inducing cross-protection to other serotypes. Both vaccines confer extensive cross-protection, and no replacement disease has been observed after introduction of these vaccines in different countries.

Research on these vaccines included large-scale efficacy trials, which enrolled over 60,000 infants.16,17 The RV5 trial was primarily conducted in the United States, developed countries in Europe, and in Latin America. The RV1 trial was conducted in sites in 11 developing countries in Latin America and in Finland. Both vaccines were found to be highly efficacious, with efficacy ranging from 85% to more than 90%. Background rates of intussusception are extremely low. Therefore, to rule out an increased risk of intussusception, very large sample sizes were necessary to allow detection of a significant increase.

Vaccine efficacy in developed countries was approximately 94%. In developing countries, however, vaccine efficacy was found to be lower. For example, efficacy of RV5 was 48% (95% CI, 22%-61%) in studies performed in 7 low-income countries in Asia, and 49% (95% CI, 19%-68%) in a RV1 study conducted in Malawi (Figure 2).16-22 There are multiple factors in these countries that may contribute to this lower efficacy. Children are more often malnourished, which may diminish their antibody response to vaccines. There may be effects of zinc or other trace element deficiencies, which is being investigated. In addition, there are many competing organisms. Often rotavirus is not alone as a pathogen, but is accompanied by other bacterial co-infections. Even though the efficacy rates are lower in developing countries, the disease burden and mortality rates are high. Consequently, more severe cases and deaths are prevented in developing countries compared with developed countries.

Figure 2

Click here for larger version of Figure 2.

Many postmarketing studies were performed in the United States after RV5 was introduced in 2006.23-28 For example, rotavirus testing data from July 2000 to June 2010 from the National Respiratory and Enteric Viruses Surveillance System was analyzed to compare rotavirus season timing and peak activity in the pre- and postvaccine introduction eras. Cumulative US data indicate that the rotavirus disease peak has been considerably blunted.29 Reduction in disease varied from 85% to 95% across geographic areas. The vaccine not only prevented disease in vaccinated infants, but also children aged 24 to 59 months who were not eligible for vaccination also experienced a decrease in rotavirus disease, exemplifying vaccine-induced herd immunity.

Data from Mexico show a reduction in deaths caused by diarrhea after introduction of the vaccine.30 In infants younger than 11 months of age, a 45% decrease in 2008 was followed by a 66% reduction in 2009 compared with the baseline rotavirus season. Similar decreases of 37% and 68% mortality reduction in 2008 and 2009, respectively, were shown in children aged 12 to 23 months. In Brazil, mean annual diarrhea mortality rates decreased by approximately 40% in children younger than 1 year in 2008 compared to prevaccine mortality rates.31 In children aged 1 to 4 years, mortality rates decreased by 33%. These encouraging results should influence decisions to use the vaccine in developing countries where diarrhea is a leading cause of childhood death.

Rotavirus Vaccine Administration in Developing Countries

There is an organization called the Global Alliance for Vaccines and Immunization (GAVI), which receives funding from multiple groups including the Gates Foundation and several donor countries.32 GAVI has a vaccine fund that provides co-funding to the poorest countries. For example, a country can get a pneumococcal vaccine for $.30 a dose, with the rest of the cost paid by GAVI. Eligible countries must provide a plan to assume the entire cost in future years. Therefore, vaccines at reasonable cost can be provided to developing countries where rotavirus disease burden and mortality rates are high.

Dosing of Rotavirus Vaccine

The ACIP recommends that the first dose of RV5 or RV1 should be given between ages 6 weeks and 14 weeks 6 days (ie, before age 15 weeks).33 The primary dose should not be given after age 15 weeks. The last dose of either vaccine should be given by 8 months 0 days, or 32 weeks. The vaccine has not been studied outside these windows. Therefore, it is important to adhere to this schedule. There is no indication that the vaccines will increase rates of intussusception if used outside the recommended ages. All recommending bodies, including the FDA, agree that the current immunization schedule should be adhered to until data are acquired.

Safety of Rotavirus Vaccine

Recent postmarketing effectiveness data from Australia indicated that, compared with historical controls, both vaccines increased rates of intussusception.34 This occurred only in infants aged 1 to < 3 months, and intussusception cases occurred more frequently 1 to 7 days (3.5-fold for RV1; 5.3-fold for RV5) and 1 to 21 days (1.5-fold for RV1; 3.5-fold for RV5) following immunization. There was no evidence of an increased risk of intussusception following immunization with either vaccine when all doses to age 9 months were combined. Intussusception rates are extremely low. Therefore, a 5-fold increase represents very few additional cases above background. Similar data have been reported from Mexico, where interim data in a postmarketing surveillance study suggest a 1.8 (99% CI, 1.0-3.1) relative risk of intussusception following the first dose of RV1. Similar to the Australian data, most cases occurred within the first 7 days after vaccination.35 After reviewing the data, the FDA and European Union concluded that the risk is very low compared to the potential benefits of both vaccines. Therefore, the FDA, the European Union, and the ACIP recommend that vaccine use should continue.

In 2010, porcine circovirus contamination was detected in both vaccines.36 This virus is found in many food products and has never been shown to cause disease in humans. After careful review of the data, all recommending bodies concluded that the vaccine is safe, and children should continue to receive both vaccines.

Summary

Rotavirus is the leading cause of hospitalized diarrhea worldwide. A majority of the 500,000 annual deaths occur in developing countries. The 2 vaccines currently available—RV5 and RV1—have been extensively tested. Subsequent to their introduction, there has been dramatic reduction in morbidity from rotavirus diarrhea in all countries where the vaccine is being used. Data from Mexico and Brazil show that there has also been a dramatic impact on mortality. A modest increase in intussusception has been observed in Mexico and Australia. However, the benefits of vaccination considerably outweigh the risk of intussusception. The ACIP continues to recommend a strict adherence to the vaccine schedule window (ie, after age 6 weeks and before age 15 weeks for the first dose, and 8 months for the last dose).

References

  1. Santosham M, Chandran A, Fitzwater S, et al. Progress and barriers for the control of diarrheal disease. Lancet. 2010;376(9734):63-67.
  2. Kapikian AZ, Hoshino Y, Chanock RM. In: Knipe DM, Howley PM, Griffin DE, eds. Fields Virology. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:1787-1825.
  3. Glass RI, Parashar UD, Bresee JS, et al. Rotavirus vaccines: current prospects and future challenges. Lancet. 2006;368(9532):323-332.
  4. Parashar UD, Hummelman EG, Breese JS, Miller MA, Glass RI. Global illness and deaths caused by rotavirus diseases in children. Emerg Infect Dis. 2003;9(5):565-572.
  5. World Health Organization. Global networks for surveillance of rotavirus gastroenteritis, 2001-2008. Wkly Epidemiol Rec. 2008;83:421-425.
  6. Rodriguez WJ, Kim HW, Arrobio JO, et al. Clinical features of acute gastroenteritis associated with human reovirus-like agent in infants and young children. J Pediatr. 1977;91(2):188-193.
  7. Mrukowicz J, Szajewska H, Vesikari T. Options for the prevention of rotavirus disease other than vaccination. J Pediatr Gastroenterol Nutr. 2008;46(suppl 2):S32-S37.
  8. Sengupta P. Rotavirus: the challenges ahead. Indian J Community Med. 2009;34(4):279-282.
  9. Clark HF, Offit PA, Glass RI, Ward RL. In: Plotkin SA, Orenstein WA, eds. Vaccines. 4th ed. New York, NY: Saunders; 2004:1327-1345.
  10. Hoshino Y, Kapikian AZ. Rotavirus serotypes: classification and importance in epidemiology, immunity, and vaccine development. J Health Popul Nutr. 2000;18(1):5-14.
  11. Dennehy PH. Rotavirus vaccines—an update. Vaccine. 2007;25(16):3137-3141.
  12. O’Ryan M, Matson DO. New rotavirus vaccines: renewed optimism. J Pediatr. 2006;149(4):448-451.
  13. Rahman M, Matthijnssens J, Nahar S, et al. Characterization of a novel P[25], G11 human group A rotavirus. J Clin Microbiol. 2005;43(7):3208-3212.
  14. Santos N, Hoshino Y. Global distribution of rotavirus serotypes/genotypes and its implication for the development and implementation of an effective rotavirus vaccine. Rev Med Virol. 2005;15(1):29-56.
  15. Centers for Disease Control and Prevention. Intussusception among recipients of rotavirus vaccine—United States, 1998-1999. MMWR Morb Mortal Wkly Rep. 1999;48(27):577-581.
  16. Vesikari T, Matson DO, Dennehy P, et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N Engl J Med. 2006;354(1):23-33.
  17. Ruiz-Palacios GM, Perez-Schael I, Velazquez FR, et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med. 2006;354(1):11-22.
  18. Tregnaghi M, Lopez P, De Leon T, et al. Oral human rotavirus vaccine RIX4414 (Rotarix) coadministered with routine EPI vaccinations including oral polio vaccine (OPV) is highly efficacious in Latin America. Poster presented at: 13th International Congress on Infectious Diseases (ICID); June 19-22, 2008; Kuala Lumpur, Malaysia.
  19. Vesikari T, Karvonen A, Prymula R, et al. Efficacy of human rotavirus vaccine against rotavirus gastroenteritis during the first 2 years of life in European infants: randomised, double-blind controlled study. Lancet. 2007;370(9601):1757-1763.
  20. Phua KB, Lim FS, Lau YL, et al. Safety and efficacy of human rotavirus vaccine during the first 2 years of life in Asian infants: randomised, double-blind, controlled study. Vaccine. 2009;27(43):5936-5941.
  21. Madhi SA, Cunliffe NA, Steele D, et al. Effect of human rotavirus vaccine on severe diarrhea in African infants. N Engl J Med. 2010;362(4):289-298.
  22. World Health Organization. Rotavirus vaccines: an update. Wkly Epidemiol Rec. 2009;84:533-540.
  23. Clark F, Lawley D, Mallette LA, DiNubile MJ, Hodinka RL. Decline in cases of rotavirus gastroenteritis presenting to the Children’s Hospital of Philadelphia after introduction of a pentavalent rotavirus vaccine. Clin Vaccine Immunol. 2009;16(3):382-386.
  24. Daskalaki I, Wood SJ, Inumerable YM, Long SS. Epidemiology of rotavirus-associated hospitalizations pre- and post-implementation of immunization: North Philadelphia, 2000-2008. In: Program and Abstracts of the 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)/Infectious Diseases Society of America (IDSA) 46th Annual Meeting; October 25-28, 2008; Washington, DC. Abstract G1-432.
  25. Patel JA, Loeffelholz M. Reduction of severe rotavirus gastroenteritis following the routine use of live, oral, pentavalent rotavirus vaccine. In: Program and Abstracts of the 48th Annual ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; Washington, DC. Abstract G1-434.
  26. Harrison CJ, Jackson M, Olson-Burgess C, Selvarangan R. Fewer 2008 hospitalizations for rotavirus (RV) in Kansas City, two years post RV vaccine. In: Program and abstracts of the 48th Annual ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; Washington, DC. Abstract G1-435.
  27. Hatch S, Fontecchio S, Gibson, L, Ellison R. Rapid decline in pediatric rotavirus cases following introduction of rotavirus vaccine. In: Program and Abstracts of the 48th Annual ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; Washington, DC. Abstract G1-436.
  28. Chang H. Reduction in New York hospitalizations for diarrhea and rotavirus. Presented at: Meeting of the Advisory Committee on Immunization Practices (ACIP); October 22-23, 2008; Atlanta, Georgia.
  29. Tate JE, Mutuc JD, Panozzo CA, et al. Sustained decline in rotavirus detections in the United States following the introduction of rotavirus vaccine in 2006. Pediatr Infect Dis J. 2011;30(suppl 1):S30-S34.
  30. Richardson V, Hernandez-Pichardo J, Quintanar-Solares M, et al. Effect of rotavirus vaccination on death from childhood diarrhea in Mexico. N Engl J Med. 2010;362(4):299-305.
  31. Lanzieri TM, Linhares AC, Costa I, et al. Impact of rotavirus vaccination on childhood deaths from diarrhea in Brazil. Int J Infect Dis. 2011;15(3):e206-e210.
  32. GAVI Alliance. http://www.gavialliance.org/. Accessed March 15, 2011.
  33. Cortese MM, Parashar UD; Centers for Disease Control and Prevention (CDC). Prevention of rotavirus gastroenteritis among infants and children: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2009;58(RR-2):1-25.
  34. Bines J. Rotavirus vaccine safety: the Austrailian experience. Presented at: 9th International Rotavirus Symposium; August 2-3, 2010; Johannesburg, South Africa.
  35. Rotarix [package insert]. Research Triangle Park, NC: GlaxoSmithKline Biologicals; 2010.
  36. Sun W. Update on CBER activities on porcine circovirus in rotavirus vaccines. Presented at: Meeting of the Advisory Committee on Immunization Practices. June 24, 2010; Atlanta, GA.