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European Society for Paediatric Infectious Diseases Consensus Recommendations for Rotavirus Vaccination in Europe: Update 2014

Vesikari, Timo MD*; Van Damme, Pierre; Giaquinto, Carlo; Dagan, Ron§; Guarino, Alfredo; Szajewska, Hania; Usonis, Vytautas**

Pediatric Infectious Disease Journal: June 2015 - Volume 34 - Issue 6 - p 635–643
doi: 10.1097/INF.0000000000000683
Vaccine Reports

The first evidence-based recommendations for rotavirus (RV) vaccination in Europe were prepared at the time of licensure of 2 live oral RV vaccines (Rotarix, GlaxoSmithKline Biologicals, and RotaTeq, Sanofi Pasteur MSD) in 2006 and published in 2008. Since then several countries in Europe and more globally have adopted universal RV vaccination of all healthy infants as part of their national immunization programs (NIPs). The experience from these NIPs has produced a wealth of post-introduction effectiveness data that, together with the evidence from prelicensure efficacy trials presented in the 2008 Recommendations, support the case of RV vaccination in Europe. The prelicensure safety trials of Rotarix and RotaTeq, each in populations of more than 60,000 infants, did not reveal risk of intussusception (IS), but postvaccination surveillance in several countries, particularly Australia and Mexico, has established that the risk of IS for both vaccines after the first dose might be between 1:50,000 and 1:80,000. Although it may be argued that the risk is acceptable vis-à-vis the great benefits of RV vaccination, this argument alone may not suffice, and every effort should be made to reduce the risk of IS. Considerable evidence, including postvaccination surveillance data from Germany, suggests that the risk of IS can be reduced by early administration of the first dose of oral RV vaccine. The previous European Society for Paediatric Infectious Diseases/European Society for Paediatric Gastroenterology, Hepatology and Nutrition recommendations held that the first dose of oral RV vaccine should be given between 6 and 12 weeks of age; this recommendation is sustained but with an emphasis toward the lower range of the recommended age, that is, preferably between 6 and 8 weeks of age. At the time of the earlier recommendations, experience of RV vaccination in premature infants and other special target groups was limited. It is now recommended with greater confidence than before that prematurely born infants should be vaccinated according to their calendar age as recommended for full-term infants. It is now strongly recommended that all HIV-infected or HIV-exposed infants should be vaccinated with oral RV vaccine. Although specific information on many immunodeficiencies is lacking, infants with known severe combined immunodeficiency should not receive live RV vaccine.

From the *Vaccine Research Centre, University of Tampere Medical School, Tampere, Finland; Centre for the Evaluation of Vaccination, Vaccine and Infectious Disease Institute, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; Department of Paediatrics, University of Padova, Padova, Italy; §Soroka University Medical Center, The Faculty of Health Sciences, Ben-Gurion University of Negev, Beer Sheva, Israel; Departments of Paediatrics, University Federico II, Naples, Italy; Department of Paediatrics, The Medical University of Warsaw, Poland; and **Centre of Paediatrics, Vilnius University, Vilnius, Lithuania.

Accepted for publication December 8, 2014

T. Vesikari has received honoraria for consultancy services and lectures, from Merck, Sanofi Pasteur MSD, GSK and Pfizer. He has been the principal investigator in clinical trials for RotaShield (Wyeth-Lederle vaccines), RotaTeq (Merck & Co., Inc.) and Rotarix (GlaxoSmithKline Biologicals). P. Van Damme has been principal investigator of vaccine studies for Merck & Co., Inc., Sanofi Pasteur, Sanofi Pasteur MSD, GSK Biologicals and Wyeth and Berna Biotech, a Crucell company, for which the University of Antwerp obtains unrestricted educational grants; he obtained speakers fees for presentations on vaccines from Sanofi Pasteur MSD, Merck and GlaxoSmithKline Biologicals are paid directly to an educational fund held by the University of Antwerp. P. Van Damme receives no personal remuneration for this work. Carlo Giaquinto has been principal investigator in epidemiological studies supported by Sanofi Pasteur MSD and GlaxoSmithKline Biologicals. He has also received honoraria for consultancy services from GlaxoSmithKline Biologicals and Sanofi Pasteur MSD. In the last 2 years, R. Dagan has received grants/research support from Berna/Crucell, Pfizer, MSD and Protea. He has been a scientific consultant for GlaxoSmithKline, Pfizer, NASVAX and MSD and a speaker for Berna/Crucell, GlaxoSmithKline and Pfizer. He is a shareholder of Protea/NASVAX. A. Guarino is a member of the Italian Rotavirus Advocacy Committee; members of his group have received travel grants to attend meetings from companies active in the field of gastroenterology, and he received research grants from Milupa, Dicofarm and GlaxoSmithKline. H. Szajewska has participated as a clinical investigator and/or advisory board member and/or consultant and/or speaker for Arla, Biogaia, Biocodex, Danone, Dicofarm, Hipp, Nestle, Nestle Nutrition Institute, Nutricia, Mead Johnson, Merck and Sequoia. V. Usonis has been principal investigator in studies supported by GlaxoSmithKline, Pfizer and Sanofi Pasteur. He has also been a scientific consultant for Baxter, GlaxoSmithKline, Merck & Co., Inc, Novartis and Sanofi Pasteur and has received sponsorship from these companies to attend scientific meetings. Development of the Recommendations consensus was financially supported by the European Society for Paediatric Infectious Diseases (ESPID).

Address for correspondence: Timo Vesikari, MD, Vaccine Research Centre, University of Tampere Medical School, University of Tampere, Biokatu 10, FIN-33014 Tampere, Finland. E-mail: timo.vesikari@uta.fi

Two live oral vaccines against rotavirus gastroenteritis (RVGE) were approved by the European Medicines Agency (EMA) in 2006: live attenuated human rotavirus (RV) vaccine (Rotarix, GlaxoSmithKline Biologicals, Rixensart, Belgium) and live human–bovine reassortant RV vaccine (RotaTeq, Sanofi Pasteur MSD, Lyon, France).

Coinciding with the introduction of the 2 new live oral RV vaccines, a group of European experts together with the European Society for Paediatric Infectious Diseases (ESPID) and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition published Evidence-Based Recommendations for Rotavirus Vaccination in Europe.1 The recommendations have now been updated and revised in the light of new experience.

Both Rotarix and RotaTeq vaccines are licensed and available for use by private practitioners throughout Europe. As of December 2013, Austria, Belgium (with 90% co-payment), Finland, Israel and Luxemburg have incorporated universal RV vaccination into the National Immunization Program (NIP) with coverage in excess of 90%. United Kingdom introduced universal RV immunization as of September 2013, and Norway and Latvia did so in January 2014. Recently, after an extensive background work,2 a universal recommendation for RV vaccination was issued for the whole of Germany. Greece has a national recommendation with 75% reimbursement. Still other countries are at different stages of consideration of introduction of RV vaccine into NIP, whereas others have reached a moderately high coverage of RV vaccination following various national, without funding, recommendations. The status of RV vaccination in Europe is described in the follow-up report of the second European Expert Meeting on Rotavirus Vaccination,3 a review paper by Parez et al,4 and a report of the third European Expert Meeting on Rotavirus Vaccination by Huppertz et al.5,6

No clinical efficacy trials of Rotarix or RotaTeq vaccines have been carried out in Europe since the licensure of these vaccines. Efficacy trials in comparable conditions, such as Japan6,7 and Argentina,8 are generally in support of the conclusions reached in prelicensure trials in Europe. Efficacy trials in Africa and Asia have generally yielded much lower efficacy end points than trials in Europe,9–11 but those results may be regarded as less relevant from the European perspective. On the other hand, postlicensure effectiveness data have now become available from several European countries and elsewhere and are considered below.

A major issue since the previous Recommendations1 is the information on intussusception (IS) during postlicensure use of RV vaccine. Postlicensure surveillance has identified that both vaccines are unequivocally associated with IS, albeit at a very low rate. It is held that with appropriate use of the live oral RV vaccines, particularly with administration at early age, the risk can be minimized.

New evidence has arisen on the RV vaccines in special target groups, such as premature infants and immunocompromised subjects, supporting and strengthening the previous recommendations.

As of 2014, several other live oral candidate RV vaccines are being investigated, but no new RV vaccines are likely to be licensed in Europe in the near future.

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OBJECTIVES

The earlier evidence-based recommendations1 were designed for use by physicians and other health care workers in the absence of or in addition to nationally published guidelines. The new consensus recommendations should also provide policy makers of European countries with the information and tools necessary to assist in decision making on RV vaccination policy and to develop or revise their own guidelines.

These recommendations pertain to the currently available RV vaccines—Rotarix and RotaTeq. The official use of the vaccines, as endorsed by EMA, is outlined in the summary of product characteristics (SPCs) available for each vaccine.12,13

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METHODOLOGY

The earlier recommendations1 were formulated according to systematic evidence-based methodology as proposed by the GRADE working group.14,15 The new recommendations consider mainly postmarketing evidence on safety and effectiveness and reflect the consensus of the authors. The final document has been approved by ESPID board and renamed ESPID Consensus Recommendations for RV vaccination in Europe.

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RATIONALE FOR RV VACCINATION OF HEALTHY INFANTS IN EUROPE

The reasons for adopting RV vaccination in Europe remain the same as in 2008, but the case has only become stronger as more evidence on the burden of disease associated with RV has accumulated in various countries.16 First, RV universally affects young children (<5 years of age), and therefore, a universal immunization policy for all infants should be adopted. There are no known risk factors that can predict progression of the disease to severe diarrhea and dehydration with sufficient sensitivity or specificity to create a “selective” immunization program.16–19 Second, other measures for the prevention of RVGE (eg, passive immunization or probiotics) have limited long-term effectiveness and are not suitable for large-scale use.20 Third, in Europe, oral rehydration solutions and medical management of infants with RVGE are widespread, yet before RV vaccination at least 87,000 young children were hospitalized each year in Europe from severe RVGE.21 Deaths also still occur from RVGE in previously healthy infants; these deaths are not acceptable given the high standard of European healthcare.

Natural infection with different RV serotypes reduces the frequency and severity of subsequent RV episodes and protects against clinically significant RV disease.22–24 Vaccination early in life, before the first RV infection, should therefore prevent most severe cases of the disease and sequelae in healthy children. Proof of this concept was demonstrated in the early RV vaccine studies of the 1980s in Europe.25,26

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RV VACCINES LICENSED FOR USE IN EUROPE

Technical descriptions of RV vaccines licensed for use in Europe, Rotarix and RotaTeq, have been compiled based on the vaccines’ SPCs, which are approved by European regulatory authorities.12,13

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Rotarix

Rotarix contains the RIX4414 strain of the human RV G1P[8] Wa strain. The RIX4414 strain was further developed by GlaxoSmithKline Biologicals from RV strain 89-12, which was originally derived from a wild-type isolate collected from a young boy in Cincinnati (OH).27 RV strain 89-12 was cloned and passaged 10 times in Vero cells to develop the RIX4414 vaccine strain.28 Rotarix is administered to infants in 2 oral doses. Each dose contains not less than 106.0 median cell culture infective dose (CCID50).13

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Porcine circovirus

In March 2010, Rotarix was announced to contain DNA of porcine circovirus 1 (PCV-1).29 This discovery resulted in temporary withdrawal of Rotarix by the FDA from the US market and also withdrawal in some European countries. Rotarix still remains available in Spain. EMA and the WHO held all the time the position that discovery of PCV-1 DNA does not constitute a safety risk. PCV-1 is not known to infect humans. The manufacturer is committed to provide PCV-free Rotarix vaccine in the future.

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RotaTeq

RotaTeq is a human–bovine reassortant vaccine developed from an original Wistar Calf 3 (WC3) strain of bovine RV.30 The vaccine contains 5 live reassortant RV strains. Four reassortants express the human VP7 of G1, G2, G3, or G4 derived from the human RV parent strains and the attachment protein VP4, P7[5], from the bovine RV parent strain. The fifth reassortant RV expresses the VP7 protein G6 from the bovine RV parent strain, and the attachment protein VP4, P1A[8], derived from the human parent strain.31 RotaTeq is given to infants as 3 oral doses. Each dose contains not less than 2.0–2.8 × 106 infectious units of each viral strain.12

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Porcine circovirus

In May 2010, RotaTeq was found to contain fragments of DNA of PCV-1 and PCV-2. The source of this contamination was traced to batches of trypsin used in the manufacturing process.32 The manufacturer is committed to changing the process and provide PCV-free vaccine.

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Prelicensure Evidence for RV Vaccine Efficacy in Healthy Infants

The safety and efficacy of Rotarix and RotaTeq for the prevention of RVGE in healthy infants were evaluated prelicensure in several randomized-controlled trials (RCTs) involving approximately 146,000 infants worldwide with strong input from Europe. The RCTs for Rotarix33–37 and for RotaTeq38–40 have been analyzed in detail in the earlier recommendations.1

In brief, the efficacy of RV vaccines against any RVGE during the first 2 years ranged from 68% to 87%; efficacy of RV vaccines against severe RVGE during the first 2 years of life ranged from 81% to 100%; and efficacy against RVGE hospitalizations during the first year ranged from 85% to 100%. For Rotarix, European data indicate that efficacy against hospitalizations up to 2 years following the second dose of vaccine was 96%.33 For RVGE emergency department visits and hospitalizations in Europe, efficacy up to 2 years following vaccination with RotaTeq was 94% and 96%, respectively.1 Efficacy against the combined endpoint of emergency department visits and hospitalizations was sustained up to 3 years in a Finnish extension study.41

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Postlicensure Evidence for RV Vaccine Effectiveness and Impact in Europe

Postlicensure experience in the WHO European region countries that have introduced universal RV immunization program (Belgium, Austria, Finland, Israel, Luxemburg and 5 Federal states of Germany) corroborates the prelicensure efficacy studies. Moreover, the impact of large scale vaccination has been observed to be greater than effectiveness in the targeted age group alone, suggesting indirect protection.

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Vaccine effectiveness

Vaccine effectiveness is defined as a measure of protection of a vaccine or vaccination program under field conditions or in routine use.

In Belgium, effectiveness of 2 doses of Rotarix vaccine against RVGE hospitalization was 90% (95% CI [confidence interval], 81–95%). Effectiveness was 91% (75–97%) in children aged 3–11 months and 90% (76–96%) in those aged ≥12 months. Effectiveness of at least 1 dose of any RV vaccine (intention to vaccinate analysis) was 91% (82–95%).42–44

In Austria, the field effectiveness of the vaccine was estimated between 61% and 98%, depending on assumptions about the unknown vaccination status (vaccination coverage between 72% and 87%).45,46 Both Rotarix and RotaTeq vaccines have been used in Austria.

In Finland, the effectiveness of RotaTeq vaccine against hospitalization for RVGE was estimated more than 95% for partially or fully vaccinated infants in the first year, whereas in the 2-year period after NIP, the RVGE cases in children eligible for vaccination were reduced by 76%.47–49

In Israel, a case control study (RVGE-positive vs. RVGE-negative; pediatric emergency room visits and hospitalizations) demonstrated that the effectiveness for those with 2 doses of RotaTeq was 60.3%. For the Jewish population, it was 78.8% versus 57.4% in the Bedouin population (P = 0.004). For Clark score more than 16 and Vesikari score of more than 15, vaccine effectiveness was 86.1% and 80.1%, respectively.50

In Germany, with low vaccine coverage (national average increased from 3% to 26% during the 4-year study period) and use of both Rotarix and RotaTeq vaccines with similar proportions, there was a significant association between RV vaccination coverage and reduction in RV morbidity.51–53

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Vaccine impact

The overall impact of RV vaccination was immediately seen in the early introducing countries Belgium and Austria.42,45

In Belgium, in 2008, RV vaccine uptake was estimated at 90%, and the number of laboratory confirmed RV cases declined by 61.4% (95% CI, 60.2–62.6%) among all age groups compared with the 2005–2006 prevaccination period.42 After 2 years of immunization in NIP, the total reduction of RVGE cases in children eligible for vaccination was 80%.54 A reduction was observed in all age groups, with the highest decline in children younger than 1 year of age (by 80.1%; 95% CI, 78.7–81.4%), comparable in the 0–5 and the 6–11 months of age (77.3% and 82.1% respectively), and lower (52%) in children aged 12–23 months. A decrease in number of cases was also observed in older children.42

In Austria, within 18 months of the universal mass vaccination program with both RV vaccines, the hospitalization rates because of RVGE have decreased in every age group in children younger than 5 years of age. In the target population for the RV vaccine (children from the seventh week up to the sixth month of life), a decrease of hospitalization rates because of RVGE of 74% was observed compared with the era before the introduction of the vaccine. Also, in children between 32 and 60 months of age, who were not eligible for the universal mass vaccination, a decrease of 22% in hospitalization rates was observed, but in children older than 5 years of age the hospitalization rates remained unchanged.45

In Finland with a high vaccination coverage of 90% in the first year and up to 97% in the second year after introduction in September 2009, the reduction of all cases of RVGE seen in hospital (outpatients and inpatients together) was 91% (including vaccine-originated diseases) in the age group eligible for vaccination and 72% in other children not eligible for vaccination because of their age.48

In Israel, 1 year after NIP initiation with RV5 (rapid vaccine uptake), the incidence of hospital admissions and pediatric emergency department visits because of RVGE were reduced by 81%, 70% and 36% for Jewish children in their first, second and third to fifth year of life, respectively. The respective figures for Bedouin children were 70%, 27% and <20%.50

In Germany, with a moderate (58%) and low (22%) vaccine uptake observed in the 5 eastern federal states and the 11 western federal states, respectively, a reduction by 36% and 25% (in eastern federal states and western federal states, respectively) was observed in the incidence of RVGE in children younger than 2 years of age. A significant reduction in RV-related hospitalizations was observed in children in the age group 6–23 months, however, with lower vaccine coverage (50%), no significant reduction was observed in RV-related hospitalizations in children too old to be vaccinated (≥2 years of age).52

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Impact on all-cause diarrhea

In Belgium, the number of all GE-driven hospital admissions and hospitalization days for acute GE declined by 33% and 36%, respectively, from prevaccination to the second year postvaccination in children ≤2 years of age.45 In Finland, after NIP, the reduction in hospitalizations because of all-cause GE was 57%, whereas the emergency department visits were reduced by 62%.48 In Israel, in the first year after introduction of RotaTeq into NIP, the reduction in incidence of hospital visits for all-cause diarrhea in the Jewish children was 44%, 46% and 36% in their first, second, and third to fifth year of life, respectively. The respective figures for Bedouin children were 43%, 30% and 24%.50

Similar data from non-European countries (US, Australia, Mexico and Brazil) generally support the experience in Europe.55–58 Important data on reduction of all-cause diarrhoeal mortality by RV vaccination have been presented from Mexico, showing a decrease of all-cause diarrhoeal deaths by 41% in infants under 1 year of age.59

Taken together, the benefits of universal RV vaccination extend beyond the immediate target group, adding to the value of RV immunization programs.

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Additional benefits

RV vaccination (a full course of RotaTeq) was recently shown to reduce the occurrence of seizures in 8–18 month-old children by 18–21%.60 The study did not separate febrile and afebrile seizures, but both are known to occur in the connection of RVGE.61 RV infection is known to spread beyond the intestines and cause RV antigenemia and RV RNAemia, with occasional detection of infectious virus in the blood.62 Furthermore, children with both antigenemia and RNAemia tend to have a more severe disease as reflected by more vomiting and higher fever.63 Altogether, the systemic nature of RV disease only emphasizes the importance of prevention by vaccination.

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Postlicensure Effect of RV Vaccination on Circulating Wild-type RV Strains

Brazil introduced universal vaccination with Rotarix in 2006, and it was soon observed that the remaining circulating RVs were almost exclusively of G2 genotype.64,65 This is consistent with the somewhat lower efficacy of Rotarix against G2 than against other G-types.34 Similar genotype replacement has been observed in Europe; in Belgium, the G2 genotype became more dominant by increasing from 5% in pre-NIP years into 30–40% in post-NIP years.64 The clinical significance of the experience in Brazil and Belgium remains uncertain as Rotarix continues to be moderately effective against severe GE associated with G2 RV.44

In addition, in Belgium, extensive use of Rotarix has been implicated as causing a shift in G1 VP7 lineage toward more distant from the G1 in the vaccine strains.66,67 The significance, if any, of this shift is not known.

Possible effect of RV vaccination on G1P[8] RV VP7 and VP4 lineages (subtypes) was investigated in Finland before and after licensure of RV vaccines and introduction of RotaTeq vaccination. RotaTeq vaccination did not appear to be related to any change of VP4 (or VP7) lineage, but the possibility of Rotarix vaccine used to a moderate extent in 2006–2009 being associated with a shift in prevalent VP4 lineage of G1P[8] could not be ruled out.68

There is no evidence of loss of vaccine effectiveness because of any changes in the circulating wild-type RVs.

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Vaccine safety

Diarrhea: For Rotarix, no difference versus placebo was observed in the incidence of diarrhea, vomiting or severe vomiting within 14 days after vaccination of any dose.28,36,69 For RotaTeq, a slight but significant increase (about 1%) in the incidence of diarrhea and vomiting (within 7-day after dose 1) was observed.38,39 The increase in diarrhea may be related to the recently described formation, in rare cases, of double reassortants between the G1 and P[8] single reassortant vaccine strains contained in RotaTeq (see below).

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Shedding and transmission

There is evidence of vaccine virus shedding for both RV vaccines, with the shedding rate of Rotarix28 being higher than that of RotaTeq and in the case of RotaTeq, the shedding being higher than that originally reported in the REST study.70,71 For Rotarix, the rate of transmission was determined in a twin study to be as high as 18%,72 but in real life there have been only very few cases of documented transmission to contacts.

For RotaTeq, the shedding issue is complicated by the discovery of double reassortants between 2 reassortant viruses included in the vaccine. In a small number of vaccines, the reassortants G1P[5] and G7P[8] may form G1P[8] reassortants on a bovine RV VP6 backbone. Such reassortants may provide an explanation for the diarrhea described in vaccine recipients in prelicensure trials and may pose a risk for children with underlying conditions.73–75 Transmission of the vaccine-derived double reassortant to a contact has also been documented.73

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Intussusception

A tetravalent rhesus–human reassortant RV vaccine, RotaShield was voluntarily withdrawn in 1999 by its manufacturer 9 months after it first became available in response to reports of IS in infants (ie, an obstruction of the bowel, due to one portion becoming telescoped within another), occurring particularly after the first dose of RotaShield.76–79

An early study estimated the risk of IS following the first dose of RotaShield to be 1 in 4300 of vaccinated infants, but later a consensus revised the figure to 1 in 10,000.79 A reappraisal has suggested that the risk of IS with RotaShield may be lower, estimated at 1 in 10,000 to 1 in 32,000 vaccinated infants.80,81 Most (80%) of the cases of IS occurred in infants who were 90 days of age or older at the time of the first dose.82

Two trials, one each for Rotarix and RotaTeq, were specifically designed to address the question of the effect of RV vaccination on risk of IS.37,38 For both vaccines, the risk of IS was not greater than that observed in placebo recipients. For Rotarix, up to 31 days after each dose of vaccine, 6 cases of IS were reported in 31,673 vaccine recipients versus 7 cases in 31,552 placebo recipients (RR = 0.8 [0.3–2.4]). Up to 1 year after each dose of Rotarix, 4 cases of IS were reported among vaccine recipients and 14 in placebo recipients (RR = 0.28 [0.1–0.8]).35 For RotaTeq, up to 42 days after each dose of vaccine, 6 cases of IS were reported among 34,035 vaccine recipients versus 5 cases in 34,003 placebo recipients (RR = 1.6 [0.4–6.4]). Up to 1 year after each dose of RotaTeq, 13 cases of IS were reported among vaccine recipients and 15 in placebo recipients (RR = 0.9 [0.4–1.9]).36 In addition, isolated occurrences of IS were detected prelicensure for both vaccines. Altogether, the prelicensure safety trials demonstrated that the risk of IS associated with Rotarix or Rotateq vaccine, if any, is smaller than for RotaShield.

Postmarketing surveillance has, however, identified a small but measurable risk of IS associated with both Rotarix and RotaTeq vaccines. Evidence from Mexico83,84 and Australia85 has placed the risk between 1:51,000 and 1:68,000 additional cases after the first dose of both vaccines; that is, lower than what was observed with RotaShield vaccine. In these studies, no increased risk of IS has been associated with the second dose of these RV vaccines. However, postlicensure surveillance of Rotarix in Brazil has not identified increased risk of IS after the first dose but has identified a small risk after the second dose of Rotarix.83 Surveillance in the US for many years failed to conclusively identify increased risk of IS associated with RotaTeq,80 but more recently a statistically significant risk has been reported.86,87

A recent analysis from the US, based on vaccine safety database data comprising 207,955 doses of Rotarix and 301,810 doses of RotaTeq, suggests increased risk of IS within 7 days of administration of Rotarix, with possibly a greater risk after the second dose. For RotaTeq, a small risk could be identified only after 3 doses combined.88

Thus, 2 studies, one in Brazil83 and another recent one in the US,88 have suggested a risk associated with the second dose of Rotarix. The explanation is not clear. However, it may be speculated that if the first dose of Rotarix does not “take,” the second dose may effectively become the first. This might happen in the presence of high levels of maternally acquired antibodies that could block the uptake of the first dose. For RotaTeq, there are no reports on increased risk of IS after the second or third dose of vaccine.

Conceivably, the risk of IS associated with the first dose of Rotarix and RotaTeq might follow a similar age-related pattern that was found for RotaShield. The study in Mexico remained equivocal for age-relation, although there was trend toward higher rate of IS occurring in infants who received the first dose after 14 weeks of age. From Australia, age-related data were not reported. However, a recent postmarketing study in Germany detected a correlation between the ages at the time of the administration of the first dose of RV vaccine. Neither vaccine showed increased risk of IS when administered before the age of 89 days, whereas the risk of IS was increased for both vaccines when the first dose was administrated between 90 and 179 days (Rotarix 4.6 [1.5–10.7] and RotaTeq 5.8 [1.2–17.1]).89

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Vaccine Coadministration

Inactivated vaccines

Both Rotarix and RotaTeq can be administered together with DTaP, DTwP, Hib vaccine, IPV, hepatitis B vaccines and pneumococcal conjugate vaccines,90,91 with no observed immune interference for any measured entity; Rotarix can also be given together with meningococcal C conjugate vaccine.92 When coadministered with other common injectable childhood vaccines, neither vaccine causes clinically significant increases in reactogenicity. There are no published reports on coadministration with Bacillus Calmette–Guérin vaccine.

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Oral poliovirus vaccine

Concomitant administration of 2 oral attenuated vaccines may result in interference with the immune response to one or both vaccines. Data from a South African study showed that concomitant administration of Rotarix and oral poliovirus vaccine (OPV) did not interfere with the immune response to OPV (for all 3 strains). OPV interfered with the immune response to Rotarix after 1 dose but not significantly after a full course (2 doses) of RV vaccine given at 10 and 14 weeks of age.93 These infants had received a birth dose of OPV. Data from a study performed in Latin America showed that concomitant administration of RotaTeq and OPV did not interfere with the immune response to OPV (for all 3 strains) and did not significantly interfere with the immune response to RotaTeq after a full course (3 doses) of RV vaccine administered at 8, 16 and 24 weeks of age.94

In a Latin American efficacy trial of Rotarix, high efficacy was seen when RV vaccine was given concomitantly with OPV.8

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Evidence for RV Vaccination in Special Target Groups

Breastfed infants

In one study, a slight decrease in vaccine take was observed in breastfed infants when compared with infants receiving only formula feeding.69 The clinical relevance of this is unclear, and the effect could largely be overcome with the additional vaccine doses. In a recent case-control study in Germany (2009), exclusive breastfeeding was identified as an independent risk factor for RV breakthrough infections.95 However, others have not found any influence of breastfeeding on RV vaccine immunogenicity and efficacy. RCTs have shown that both RV vaccines licensed for use in Europe can be administered to infants who are breastfed without affecting the efficacy of the vaccines: normal breastfeeding was not altered for infants participating in large-scale clinical investigations of both vaccines.34–40 Breastfeeding did not reduce the efficacy of the RV vaccine in a European multi-country randomized, placebo-controlled trial (Czech Republic, Finland, France, Germany, Italy and Spain); the immunogenicity and vaccine efficacy were equally high in breastfed and exclusively formula-fed infants in the first RV season.96 In addition, studies in India and South Africa have shown that abstention from breastfeeding for at least 1 hour before and after each vaccination dose had no significant effect on immune response to RV vaccine.97,98

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HIV-infected infants

Recent studies in developing countries have shown that RVGE is more common and more severe in HIV-infected children than in uninfected children.99–101 Immunogenicity, efficacy and safety studies with both Rotarix and RotaTeq have been carried out in African countries including both in utero exposed HIV-infected and HIV-uninfected infants.102–104 Despite the study limitations because of the low number of HIV-infected children included the results suggest that HIV-infected children have an immune response to RV vaccines comparable with HIV-negative children. Vaccines are well tolerated, and their administration does not increase HIV-related immunosuppression.102 Similar results have also been observed in HIV-infected adults.105 A recent study in South Africa demonstrated that the effectiveness of Rotarix vaccine in HIV-exposed uninfected children was not different from HIV-uninfected children. The study was not powered to detect vaccine effectiveness in HIV-infected children.106

In Europe, the successful implementation of prevention of mother to children transmission of HIV resulted in a dramatic reduction in the number of new HIV-infected infants, despite the overall increase in the number of pregnancies in HIV-positive women, mainly of African origin. Moreover, the widespread availability of testing for early diagnosis allows the identification of most cases of HIV infection by 6–8 weeks of age with a rapid initiation of antiretroviral therapy greatly reducing the risk of HIV progression and of severe immunodeficiency early in life. In these settings, RV vaccination for asymptomatic HIV-infected children should be considered similar to HIV-negative ones.

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Infants with severe immunodeficiency

In children with severe combined immunodeficiency, RV vaccination is contraindicated for the increased risk of vaccine strain-associated diarrhea.107–109 No specific data are available for other complete or partial B and/or T cell immunodeficiencies (eg, X-linked agammaglobulinemia, Di George syndrome, Wiskott–Aldrich syndrome, ataxia-telangiectasia and others). However, RV vaccination is contraindicated if these conditions are already diagnosed at the time of immunization. In infants with confirmed family history of immunodeficiency, it is suggested to delay the vaccination until a possible diagnosis has been ruled out, but not later than 3 months of age.

Children with selective IgA deficiency may asymptomatically have prolonged excretion of RV vaccine virus. Similarly, mice with IgA deficiency do not develop a protective immunity against RV and can excrete the virus for a much longer period than immunocompetent mice.110The presence of IgA deficiency is usually undiagnosed in the first months of life at the age of RV immunization.

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Premature infants

RV infection in very premature infants may, rarely, be associated with serious complications, such as necrotizing enterocolitis and secondary bacteremia. In addition, premature infants are exposed to a proportionally higher risk of nosocomial infection than full-term infants.111

There is evidence that both licensed RV vaccines can be safely given to early premature (<32 weeks of gestational age) and to premature (<36 weeks of gestational age) infants when administered according to the schedule following the infants’ calendar age.112–114 Overall, safety, immunogenicity and efficacy data in premature infants are comparable with those in full-term infants.

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RECOMMENDATIONS

Healthy Infants: Routine Administration

Recommendation 1: It is strongly recommended that RV vaccination should be offered to all healthy infants in Europe, and that RV vaccination is offered equally for breast-fed and formula-fed infants without interruption of breast feeding.

Comment: In the countries that have introduced RV vaccination, the excellent results on impact come actually from populations that are predominantly breast feeding at the time of vaccination.

In Europe, both licensed RV vaccines (Rotarix and RotaTeq) have shown high efficacy and effectiveness, breast-fed infants with only a slight decrease in vaccine take between breast-fed or formula-fed infants. Studies in India and South Africa have shown that abstention from breastfeeding for at least 1 hour before and after each vaccination dose had no significant effect on immune response to RV vaccine. Therefore, it is not recommended to withhold breastfeeding before vaccination

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Concomitant Administration

Recommendation 2: Both RV vaccines licensed for use in Europe can be administered separately or concomitantly with inactivated, injectable childhood vaccines and, probably, Bacillus Calmette–Guérin vaccine. RV vaccination can be integrated into all European vaccination schedules.

Comment: It has been shown that RV vaccines can be co-administered with commonly used, injectable childhood vaccines without affecting efficacy or safety of both coadministered vaccines, and, therefore can be integrated into the existing immunization schedules with injectable vaccines. However, it is also possible to give RV alone, as exemplified by the Finnish schedule starting at 2 months with RV vaccine alone followed by 3 and 5 months concomitantly with injectable vaccines.

Recommendation 3: In European countries where OPV is in use, concomitant administration with RV vaccine is not suggested for the first dose.

Comment: There is evidence that when concomitantly administered the uptake of the first dose of RV vaccine may be suppressed by OPV. However, after a full course of RV vaccination (2 doses of Rotarix or 3 doses of RotaTeq) reduction of immune response is no longer significant. Therefore, separate administration of RV vaccine and OPV is recommended whenever feasible.

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Dosing Schedule

Recommendation 4: It is recommended that, for safety, the first dose of RV vaccine should be given between the age of 6 and 12 weeks, preferably at the age of 6–8 weeks, and the full schedule (Rotarix 2 doses; RotaTeq 3 doses) should be completed latest by the age of 24 weeks, but preferably earlier.

Comment: Although other recommendations and the SPCs of both Rotarix and RotaTeq allow vaccination of older infants up to 15 or 16 weeks of age for the first dose, it is noted that there is no positive evidence of vaccine safety for IS in the age group 13–16 weeks of age. To the contrary, a recent study from Germany89 suggests that there is no detectable risk of IS in infants receiving their first dose of RV vaccine at ≤89 days of age, but there is a small risk of IS associated with both Rotarix and RotaTeq when the first dose is given between ages of 90 and179 days. Moreover, RotaShield vaccine with a clear overall association with IS did not show risk of IS if given below the age of 59 days.82

Evidence for efficacy of the available RV vaccines is limited to a full schedule. However, incomplete dosing of RV vaccines will result in considerable efficacy against RV gastroenteritis.

There are no data available concerning a mixed schedule (Rotarix first followed by RotaTeq or vice versa); therefore, no evidence-based recommendation can be issued with regard to interchangeability of these vaccines. However, in the event that a mixed schedule is given, it is recommended that the full course should include 3 doses. There is no known risk or harm associated with mixed schedule.

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Vaccination of Premature Infants

Recommendation: RV vaccination is recommended for (early) premature infants, according to their calendar age (as recommended for healthy full-term infants), including those still being hospitalized at the calendar age for the first RV vaccine administration. In such cases, precautions should be taken to avoid transmission to high risk contacts.

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Vaccination of Infants with Immunodeficiency Underlying Conditions

Recommendation: All HIV-exposed infants should be vaccinated regardless of their HIV-infection status at appropriate calendar age.

Recommendation: For infants with severe immunodeficiency, RV vaccination is not recommended.

This recommendation places a higher value on avoiding side effects in infants, potentially at high risk of RV vaccine-related severe diarrhea as observed in patients with severe combined immunodeficiency.

Because of the absence of specific data, this recommendation has been reached by extrapolation of evidence from other live vaccines.

Comment: Prelicensure clinical trials have been performed in healthy infants and have not investigated the possibility of using RV vaccines in infants with underlying conditions (eg, chronic diseases, malformations of the gastrointestinal tract, those having undergone abdominal surgery or those with food intolerance). Therefore, because of insufficient evidence at present, no specific recommendation can be made for RV vaccination of infants with underlying conditions.

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Continued Safety Surveillance

Recommendation: It is recommended that continued monitoring for serious adverse events should be in place for RV vaccination.

Comment: Given that IS is the most common cause of intestinal obstruction in young infants, cases will naturally occur within the timeframe of RV vaccination. Surveillance systems will, therefore, need to distinguish between those cases temporally linked by chance with RV vaccination and those that may have occurred as a direct result of the vaccine.

Postmarketing surveillance should be tuned to collection of further data on the relationship between the number of doses, age at dosing, and occurrence of IS. Moreover, surveillance systems may be needed to identify any, as yet unknown, adverse consequences of RV vaccination.

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ACKNOWLEDGMENTS

Dr. Jacek Mrukowicz and Dr. Jim Gray were part of the Group that developed earlier evidence based recommendations for rotavirus vaccination in Europe, referenced here,1 and their contribution is gratefully acknowledged. We also thank Maria Hemming BM for technical support and Katri Rouhiainen for secretarial help.

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Rotavirus; Gastroenteritis; Vaccine; Guideline; Recommendation

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