The Data Sheet for Rotavirus Vaccine
ROTARIX is a liquid suspension of the live attenuated RIX4414 strain of human rotavirus of the G1P type for use in the prevention of rotavirus gastro-enteritis. The virus strain derived from the 89-12 strain is obtained by propagation on a well-characterised Vero cell line.
ROTARIX is presented as a clear, colourless liquid, free of visible particles, for ORAL administration only.
Each 1.5 mL dose of the vaccine contains not less than 106.0 CCID50 (cell culture infectious dose 50%) of the RIX 4414 strain of human rotavirus. The vaccine also contains sucrose, di-sodium adipate, Dulbecco’s Modified Eagle Medium and sterile water.
(VAN's note: Vero cell line is monkey kidney tissue).
The manufacture of this product includes exposure to bovine derived materials at the very early steps of the production process. No bovine materials are used in routine production. No evidence exists that any case of vCJD (considered to be the human form of bovine spongiform encephalopathy) has resulted from the administration of any vaccine product.
(VAN's note: Cases of vCJD have occured in clusters in people who have had the same batch of another type of vaccine and scientists agree that the most likely form of transmission is via injection or IV - see this http://www.youtube.com/watch?v=2GpD0wt3LXM).
Unintended Pig Virus in the Rotavirus Vaccine
Porcine Circovirus type 1 (PCV-1) material has been detected in ROTARIX vaccine. PCV-1 is not known to cause disease in animals and is not known to infect or cause disease in humans. There is no evidence that the presence of PCV-1 poses a safety risk.
Rotavirus is likely to affect all children up to the age of five years of age. The peak incidence of rotavirus gastro-enteritis is between 6-24 months of age. Dehydration from rotavirus gastro-enteritis can lead to hospitalisation, which is most common in children under 2 years of age.
They Don't Know if or How Vaccine Antibodies Protect Against Rotavirus!
The immunologic mechanism by which ROTARIX protects against rotavirus gastro-enteritis is not entirely understood. A relationship between antibody responses to rotavirus vaccination and protection against rotavirus gastro-enteritis has not been established.
ROTARIX, which is derived from the most common human rotavirus type G1P, has been demonstrated to induce protective immunity against both the G1P type, and also against other non-G1 prevalent strains (See Clinical Trials).
(VAN's Note: for the manufacturer's efficacy trial tables see: http://www.medsafe.govt.nz/profs/datasheet/r/Rotarixvac.pdf).
ROTARIX should not be administered to subjects with known hypersensitivity to any components of the vaccine (see DESCRIPTION), or to subjects having shown signs of hypersensitivity after previous administration of rotavirus vaccines.
ROTARIX should not be administered to subjects with any history of chronic gastrointestinal disease including any uncorrected congenital malformation (such as Meckel’s diverticulum) of the gastrointestinal tract.
Subjects with Severe Combined Immunodeficiency (SCID) disorder (see ADVERSE REACTIONS).
As with other vaccines, administration of ROTARIX should be postponed in subjects suffering from acute severe febrile illness. The presence of a minor infection, such as a cold, is not a contraindication for immunisation.
ROTARIX should under no circumstances be injected.
The administration of ROTARIX should be postponed in subjects suffering from diarrhoea or vomiting.
Administration of ROTARIX may be considered with caution in infants with gastrointestinal illnesses, when, in the opinion of the physician, the risk of rotavirus infection by withholding the vaccine entails a greater risk to the infant. No safety or efficacy data are available for the administration of ROTARIX to infants with gastrointestinal illnesses.
The risk of intussusception has been evaluated in a large safety trial (including 63,225 infants) conducted in Latin America and Finland. No increased risk of intussusception was observed in this clinical trial following administration of Rotarix when compared with placebo (See Adverse Reactions).
However, post-marketing safety data indicate a possible increased risk of intussusception in the 31-day period following the administration of the first dose of ROTARIX. It has not been established whether ROTARIX affects the overall incidence of intussusception. (See ADVERSE REACTIONS).
Therefore, as a precaution, healthcare professionals should follow-up on any symptoms indicative of intussusception (severe abdominal pain, persistent vomiting, bloody stools, abdominal bloating and/or high fever). Parents/guardians should be advised to promptly report such symptoms.
Administration of ROTARIX in immunosupressed infants, including infants on immunosuppressive therapy, should be based on careful consideration of potential benefits and risks.
The Vaccine Sheds and Can Infect Others, Including Newborns and Elderly!
Excretion of the vaccine virus in the stools occurs after vaccination and lasts for 10 days on average with peak excretion around the 7th day. Viral antigen particles detected by ELISA were found in 50% of stools after the first dose and 4% of stools after the second dose. When these stools were tested for the presence of live vaccine strain, 17% were positive.
In two comparative controlled trials, vaccine shedding after vaccination with ROTARIX liquid formulation was comparable to that observed after vaccination with ROTARIX lyophilised formulation. There is a potential risk for transmission to non-vaccinated contacts.
In clinical trials, cases of transmission of excreted vaccine virus to seronegative contacts of vaccinees have been observed without causing any clinical symptoms. Therefore ROTARIX should be administered with caution to infants with close contacts who are immunodeficient, such as individuals with malignancies, or who are otherwise immunocompromised or receiving immunosuppressive therapy. Contacts of recent vaccinees should be advised to observe careful hygiene (including washing their hands) when changing children’s nappies.
The Vaccine Might Not Protect You and They Don't Know How Long It Lasts For
As with any vaccine, a protective immune response may not be elicited in all vaccinees (see CLINICAL TRIALS).
The extent of protection that ROTARIX might provide against rotavirus strains that have not been circulating in clinical trials is currently unknown (see CLINICAL TRIALS).
ROTARIX does not protect against gastro-enteritis due to pathogens other than rotavirus.
Carcinogenicity and Mutagenicity
ROTARIX has not been evaluated for carcinogenicity or mutagenicity.
(VAN's Note: This means that it hasn't been safety tested to see if it causes cancer or if it mutates into another illness).
Impairment of Fertility
ROTARIX has not been evaluated for its potential to impair fertility.
(VAN's Note: This means it has not been safety tested to see if it causes infertility).
ROTARIX has not been evaluated for genotoxicity.
(VAN's Note: This means that it hasn't been safety tested to see if it damages DNA).
Use in Pregnancy (Category B2):
ROTARIX is not intended for use in adolescents or adults. Thus human data on use during pregnancy are not available and animal reproduction studies have not been performed.
Use in Lactation:
ROTARIX is not intended for use in adolescents or adults. Thus human data on use during lactation are not available.
Based on evidence generated in clinical trials, breast-feeding does not reduce the protection against rotavirus gastro-enteritis afforded by ROTARIX. Therefore, breast-feeding may be continued during the vaccination schedule.
ROTARIX is intended for use in infants in the first six months of life. ROTARIX should not be administered to children older than 24 weeks of age as safety has not been demonstrated, particularly in relation to risk of intussusception.
Use in the Elderly
ROTARIX is not intended for use in the elderly. Thus human data on use in the elderly are not available.
Co-administration studies have demonstrated that ROTARIX can be given concomitantly with any of the following administered either as monovalent or as combination vaccines: diphtheria-tetanus-acellular pertussis vaccine (DTPa), Haemophilus influenzae type b vaccine (Hib), inactivated polio vaccine (IPV), hepatitis B vaccine (HBV), hexavalent vaccines DTPa-HBV-IPV/Hib, pneumococcal conjugate vaccine and meningococcal serogroup C conjugate vaccine. The studies demonstrated that the immune responses and the safety profiles of the administered vaccines were unaffected.
Clinical studies, involving more than 2,000 subjects, were performed where ROTARIX and oral polio vaccine (OPV) were administered two weeks apart. The immune response to ROTARIX and OPV was unaffected. In three immunogenicity studies, involving approximately 1,200 subjects, ROTARIX was concomitantly administered with OPV. The immune response to OPV, as well as the response to ROTARIX after the second dose, were unaffected. ROTARIX can be concomitantly administered with OPV if this is in accordance with local recommendations. In the absence of local recommendations, an interval of two weeks between the administration of OPV and ROTARIX should be respected.
Although antibodies to rotavirus may be detected in breast milk, the available data show no reduction in efficacy when ROTARIX is administered to breast-fed infants.
Adverse reactions are thought of as very common if they affect more than one in 10 people, common if they affect more than one in 100 but less than one in 10, uncommon if they affect more than one in 1000 but less than one in 100, rare if they affect more than one in 10,000 but less than one in 1000 and very rare if they affect less than one in 10,000.
Uncommon: flatulence, abdominal pain
Skin and subcutaneous tissue disorders:
(VAN's Note: This vaccine is to protect against diarrhoea and it's most common side-effect is diarrhoea).
Safety in preterm infants
In a clinical study, 1009 preterm infants were administered ROTARIX lyophilised formulation or placebo (198 were 27-30 weeks gestational age and 801 were 31-36 weeks gestational age). The first dose was administered from 6 weeks after birth. Serious adverse events were observed in 5.1% of recipients of ROTARIX as compared with 6.8% of placebo recipients. Similar rates of solicited and unsolicited symptoms were observed in ROTARIX and placebo recipients. No cases of intussusception were reported.
(VAN's Note: They don't say what the placebo was. In vaccine trials it is usually another vaccine or aluminium or another adjuvant - NOT a totally unvaccinated control).
Safety in infants with human immunodeficiency (HIV) infection
In a clinical study, 100 infants with HIV infection were administered ROTARIX lyophilised formulation or placebo. The safety profile was similar between ROTARIX and placebo recipients.
(VAN's Note: This contradicts what they say in the same data sheet about the danger of shedding and other problems in the immuno-compromised).
gastroenteritis with vaccine viral shedding in infants with Severe Combined Immunodeficiency
*Preliminary data from a large post-marketing epidemiological safety study in Mexico indicate a possible increased risk of intussusception in the 31 day period following the first dose. The relative incidence of intussusception with ROTARIX in the 31 day period following the administration of the first dose was 1.752 (99%CI 0.997-3.08) compared to the remaining period up to 1 year of age. Spontaneous reports of intussusception have been received mostly within 7 days after the first dose. These observations are limited to the first dose and not seen following administration of the second dose. It has not been established whether ROTARIX affects the overall incidence of intussusception (see PRECAUTIONS).
DOSAGE AND ADMINISTRATION
The vaccination course consists of two doses. The first dose should be given between 6 and 14 weeks of age. The interval between the two doses should not be less than 4 weeks. The vaccine course should be completed by the age of 24 weeks as safety has not been assessed in older children.
ROTARIX may be given to preterm infants with the same posology (see Adverse reactions).
In clinical trials, spitting or regurgitation of the vaccine has rarely been observed and, under such circumstances, a replacement dose was not given. However, in the unlikely event that an infant spits out or regurgitates most of the vaccine dose, a single replacement dose may be given at the same vaccination visit.
It is strongly recommended that infants who receive a first dose of ROTARIX complete the 2-dose regimen with ROTARIX.
ROTARIX is for ORAL use only.
ROTARIX SHOULD UNDER NO CIRCUMSTANCES BE INJECTED.
There are no restrictions on the infant’s consumption of food or liquid, including breast milk, either before or after vaccination.
Rotarix Oral Vaccine Data Sheet, GlaxoSmithKline, 1st April 2011.
Data From the FDA
A demonstrated history of hypersensitivity to any component of the vaccine.
Infants who develop symptoms suggestive of hypersensitivity after receiving a dose of ROTARIX should not receive further doses of ROTARIX.
Gastrointestinal Tract Congenital Malformation
Infants with a history of uncorrected congenital malformation of the gastrointestinal tract (such as Meckel’s diverticulum) that would predispose the infant for intussusception should not receive ROTARIX.
History of Intussusception
Infants with a history of intussusception should not receive ROTARIX [see Warnings and Precautions (5.5)]. In postmarketing experience, intussusception resulting in death following a second dose has been reported following a history of intussusception after the first dose [see Adverse Reactions (6.2)].
Severe Combined Immunodeficiency Disease
Infants with Severe Combined Immunodeficiency Disease (SCID) should not receive ROTARIX. Postmarketing reports of gastroenteritis, including severe diarrhea and prolonged shedding of vaccine virus, have been reported in infants who were administered live, oral rotavirus vaccines and later identified as having SCID [see Adverse Reactions (6.2)].
WARNINGS AND PRECAUTIONS
ROTARIX is available with a vial of lyophilized vaccine and 2 types of prefilled oral applicators of liquid diluent. One type of applicator has a tip cap which may contain natural rubber latex. The other type has both a tip cap and a rubber plunger which contains dry natural latex rubber. Use of either of these oral applicators may cause allergic reactions in latex-sensitive individuals. The vial stopper does not contain latex.
Administration of ROTARIX should be delayed in infants suffering from acute diarrhea or vomiting.
Safety and effectiveness of ROTARIX in infants with chronic gastrointestinal disorders have not been evaluated.
Safety and effectiveness of ROTARIX in infants with known primary or secondary immunodeficiencies, including infants with human immunodeficiency virus (HIV), infants on immunosuppressive therapy, or infants with malignant neoplasms affecting the bone marrow or lymphatic system have not been established.
Shedding and Transmission
Rotavirus shedding in stool occurs after vaccination with peak excretion occurring around day 7 after dose 1.
One clinical trial demonstrated that vaccinees transmit vaccine virus to healthy seronegative contacts [see Clinical Pharmacology (12.2)].
The potential for transmission of vaccine virus following vaccination should be weighed against the possibility of acquiring and transmitting natural rotavirus. Caution is advised when considering whether to administer ROTARIX to individuals with immunodeficient close contacts, such as individuals with malignancies, primary immunodeficiency or receiving immunosuppressive therapy.
Following administration of a previously licensed oral live rhesus rotavirus-based vaccine, an increased risk of intussusception was observed.1 The risk of intussusception with ROTARIX was evaluated in a pre-licensure randomized, placebo-controlled safety study (including 63,225 infants) conducted in Latin America and Finland. No increased risk of intussusception was observed in this clinical trial following administration of ROTARIX when compared with placebo. [See Adverse Reactions (6.1).]
In a postmarketing, observational study conducted in Mexico, cases of intussusception were observed in temporal association within 31 days following the first dose of ROTARIX, with a clustering of cases in the first 7 days. [See Adverse Reactions (6.2).]
In worldwide passive postmarketing surveillance, cases of intussusception have been reported in temporal association with ROTARIX [see Adverse Reactions (6.2)].
Safety and effectiveness of ROTARIX when administered after exposure to rotavirus have not been evaluated.
(VAN's Note: How would they know since stools are rarely evaluated when an infant has gastroenteritis?).
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine, and may not reflect the rates observed in practice. As with any vaccine, there is the possibility that broad use of ROTARIX could reveal adverse reactions not observed in clinical trials.
Solicited and unsolicited adverse events, serious adverse events and cases of intussusception were collected in 7 clinical studies. Cases of intussusception and serious adverse events were collected in an additional large safety study. These 8 clinical studies evaluated a total of 71,209 infants who received ROTARIX (N = 36,755) or placebo (N = 34,454). The racial distribution for these studies was as follows: Hispanic 73.4%, white 16.2%, black 1.0%, and other 9.4%; 51% were male. Solicited Adverse Events: In 7 clinical studies, detailed safety information was collected by parents/guardians for 8 consecutive days following vaccination with ROTARIX (i.e., day of vaccination and the next 7 days). A d.iary card was completed to record fussiness/irritability, cough/runny nose, the infant’s temperature, loss of appetite, vomiting, or diarrhea on a daily basis during the first week following each dose of ROTARIX or placebo.
Adverse events among recipients of ROTARIX and placebo occurred at similar rates.
Fussiness and Irritability occured in 52% of infants vaccinated and in 52% of the placebo (VAN's Note: The FDA don't say what the placebo was).
Cough and Runny Nose occured in 28% of infants vaccinated and 30% of the placebo.
Fever occured in 25% of infants vaccinated and 33% of the placebo.
Loss of appetite occured in 25% of infants vaccinated and 25% of the placebo.
Vomiting occured in 13% of infants vaccinated and 11% of the placebo.
Diarrhoea occured in 4% of infants vaccinated and 3% of the placebo.
Unsolicited Adverse Events:
Infants were monitored for unsolicited serious and non-serious adverse events that occurred in the 31-day period following vaccination in 7 clinical studies. The following adverse events occurred at a statistically higher incidence (95% Confidence Interval [CI] of Relative Risk excluding 1) among recipients of ROTARIX (N = 5,082) as compared with placebo recipients (N = 2,902): irritability (ROTARIX 11.4%, placebo 8.7%) and flatulence (ROTARIX 2.2%, placebo 1.3%). Serious Adverse Events (SAEs): Infants were monitored for serious adverse events that occurred in the 31-day period following vaccination in 8 clinical studies. Serious adverse events occurred in 1.7% of recipients of ROTARIX (N = 36,755) as compared with 1.9% of placebo recipients (N = 34,454). Among placebo recipients, diarrhea (placebo 0.07%, ROTARIX 0.02%), dehydration (placebo 0.06%, ROTARIX 0.02%), and gastroenteritis (placebo 0.3%, ROTARIX 0.2%) occurred at a statistically higher incidence (95% CI of Relative Risk excluding 1) as compared with recipients of ROTARIX.
During the entire course of 8 clinical studies, there were 68 (0.19%) deaths following administration of ROTARIX (N = 36,755) and 50 (0.15%) deaths following placebo administration (N = 34,454). The most commonly reported cause of death following vaccination was pneumonia, which was observed in 19 (0.05%) recipients of ROTARIX and 10 (0.03%) placebo recipients (Relative Risk: 1.74, 95% CI: 0.76, 4.23).
In a controlled safety study conducted in Latin America and Finland, the risk of intussusception was evaluated in 63,225 infants (31,673 received ROTARIX and 31,552 received placebo). Infants were monitored by active surveillance including independent, complementary methods (prospective hospital surveillance and parent reporting at scheduled study visits) to identify potential cases of intussusception within 31 days after vaccination and, in a subset of 20,169 infants (10,159 received ROTARIX and 10,010 received placebo), up to one year after the first dose.
No increased risk of intussusception following administration of ROTARIX was observed within a 31-day period following any dose, and rates were comparable to the placebo group after a median of 100 days (Table 2). In a subset of 20,169 infants (10,159 received ROTARIX and 10,010 received placebo) followed up to one year after dose 1, there were 4 cases of intussusception with ROTARIX compared with 14 cases of intussusception with placebo [Relative Risk: 0.28 (95% CI: 0.10, 0.81)]. All of the infants who developed intussusception recovered without sequelae.
Kawasaki disease has been reported in 18 (0.035%) recipients of ROTARIX and 9 (0.021%) placebo recipients from 16 completed or ongoing clinical trials. Of the 27 cases, 5 occurred following ROTARIX in clinical trials that were either not placebo-controlled or 1:1 randomized. In placebo-controlled trials, Kawasaki disease was reported in 17 recipients of ROTARIX and 9 placebo recipients [Relative Risk: 1.71 (95% CI: 0.71, 4.38)]. Three of the 27 cases were reported within 30 days post-vaccination: 2 cases (ROTARIX = 1, placebo = 1) were from placebo-controlled trials [Relative Risk: 1.00 (95% CI: 0.01, 78.35)] and one case following ROTARIX was from a non-placebo-controlled trial. Among recipients of ROTARIX, the time of onset after study dose ranged 3 days to 19 months.
The temporal association between vaccination with ROTARIX and intussusception was evaluated in a hospital-based active surveillance study that identified infants with intussusception at participating hospitals in Mexico.
Using a self-controlled case series method, the incidence of intussusception during the first 7 days after receipt of ROTARIX and during the 31-day period after receipt of ROTARIX was compared to a control period. The control period was from birth to one year, excluding the pre-defined risk period (first 7 days or first 31 days post-vaccination, respectively).
Over a 2-year period, the participating hospitals provided health services to approximately 1 million infants under 1 year of age. Among 750 infants with intussusception, the relative incidence of intussusception in the 31-day period after the first dose of ROTARIX compared to the control period was 1.96 (95.5% CI: 1.46, 2.63)]; the relative incidence of intussusception in the first 7 days after the first dose of ROTARIX compared to the control period was 6.07 (95.5% CI: 4.20, 8.63).
The Mexico study did not take into account all medical conditions that may predispose infants to intussusception. The results may not be generalizable to US infants who have a lower background rate of intussusception than Mexican infants. However, if a temporal increase in the risk for intussusception following ROTARIX similar in magnitude to that observed in the Mexico study does exist in US infants, it is estimated that approximately 1 to 3 additional cases of intussusception hospitalizations would occur per 100,000 vaccinated infants in the US within 7 days following the first dose of ROTARIX. In the first year of life, the background rate of intussusception hospitalizations in the US has been estimated to be approximately 34 per 100,000 infants.
Worldwide passive postmarketing surveillance data also suggest that most cases of intussusception reported following ROTARIX occur in the 7-day period after the first dose.
The following adverse events have been reported since market introduction of ROTARIX. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccination with ROTARIX.
Intussusception (including death), recurrent intussusception (including death), hematochezia, gastroenteritis with vaccine viral shedding in infants with Severe Combined Immunodeficiency Disease (SCID).
Blood and Lymphatic System Disorders: Idiopathic thrombocytopenic purpura. Vascular Disorders: Kawasaki disease. General Disorders and Administration Site Conditions: Maladministration.
Concomitant Vaccine Administration
In clinical trials, ROTARIX was administered concomitantly with US-licensed and non-US-licensed vaccines. In a US coadministration study in 484 infants, there was no evidence of interference in the immune responses to any of the antigens when PEDIARIX® [Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Hepatitis B (Recombinant) and Inactivated Poliovirus Vaccine], a US-licensed 7-valent pneumococcal conjugate vaccine (Wyeth Pharmaceuticals Inc.), and a US-licensed Hib conjugate vaccine (Sanofi Pasteur SA) were coadministered with ROTARIX as compared with separate administration of ROTARIX.
Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune response to ROTARIX. [See Warnings and Precautions (5.3).]
USE IN SPECIFIC POPULATIONS
Pregnancy Category C
Animal reproduction studies have not been conducted with ROTARIX. It is also not known whether ROTARIX can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.
Safety and effectiveness of ROTARIX in infants younger than 6 weeks or older than 24 weeks of age have not been evaluated.
The effectiveness of ROTARIX in pre-term infants has not been established. Safety data are available in pre-term infants (ROTARIX = 134, placebo = 120) with a reported gestational age 36 weeks. These pre-term infants were followed for serious adverse events up to 30 to
90 days after dose 2. Serious adverse events were observed in 5.2% of recipients of ROTARIX as compared with 5.0% of placebo recipients. No deaths or cases of intussusception were reported in this population.
ROTARIX (Rotavirus Vaccine, Live, Oral), for oral administration, is a live, attenuated rotavirus vaccine derived from the human 89-12 strain which belongs to G1P type. The rotavirus strain is propagated on Vero cells. After reconstitution, the final formulation (1 mL) contains at least 106.0 median Cell Culture Infective Dose (CCID50) of live, attenuated rotavirus.
The lyophilized vaccine contains amino acids, dextran, Dulbecco’s Modified Eagle Medium (DMEM), sorbitol, and sucrose. DMEM contains the following ingredients: sodium chloride, potassium chloride, magnesium sulfate, ferric (III) nitrate, sodium phosphate, sodium pyruvate, D-glucose, concentrated vitamin solution, L-cystine, L-tyrosine, amino acids solution, L-glutamine, calcium chloride, sodium hydrogenocarbonate, and phenol red.
In the manufacturing process, porcine-derived materials are used. Porcine circovirus type 1 (PCV-1) is present in ROTARIX. PCV-1 is not known to cause disease in humans.
The liquid diluent contains calcium carbonate, sterile water, and xanthan. The diluent includes an antacid component (calcium carbonate) to protect the vaccine during passage through the stomach and prevent its inactivation due to the acidic environment of the stomach.
They Don't Know How it Works or If Antibodies Mean Immunity
The exact immunologic mechanism by which ROTARIX protects against rotavirus gastroenteritis is unknown [see Clinical Pharmacology (12.2)]. ROTARIX contains a live, attenuated human rotavirus that replicates in the small intestine and induces immunity.
Pharmacodynamics Immunogenicity: A relationship between antibody responses to rotavirus vaccination and protection against rotavirus gastroenteritis has not been established.
Shedding and Transmission:
A prospective, randomized, double-blind, placebo-controlled study was performed in the Dominican Republic in twins within the same household to assess whether transmission of vaccine virus occurs from a vaccinated infant to a non-vaccinated infant. One hundred pairs of healthy twins 6 to 14 weeks of age (gestational age 32 weeks) were randomized with one twin to receive ROTARIX (N = 100) and the other twin to receive placebo (N = 100). Twenty subjects in each arm were excluded for reasons such as having rotavirus antibody at baseline. Stool samples were collected on the day of or 1 day prior to each dose, as well as 3 times weekly for 6 consecutive weeks after each dose of ROTARIX or placebo. Transmission was defined as presence of the vaccine virus strain in any stool sample from a twin receiving placebo.
Transmitted vaccine virus was identified in 15 of 80 twins receiving placebo (18.8% [95% CI: 10.9, 29.0]). Median duration of the rotavirus shedding was 10 days in twins who received ROTARIX as compared to 4 days in twins who received placebo in whom the vaccine virus was transmitted. In the 15 twins who received placebo, no gastrointestinal symptoms related to transmitted vaccine virus were observed.
Carcinogenesis, Mutagenesis, Impairment of Fertility
ROTARIX has not been evaluated for carcinogenic or mutagenic potential, or for impairment of fertility.
The data demonstrating the efficacy of ROTARIX in preventing rotavirus gastroenteritis come from 24,163 infants randomized in two placebo-controlled studies conducted in 17 countries in Europe and Latin America. In these studies, oral polio vaccine (OPV) was not coadministered; however, other routine childhood vaccines could be concomitantly administered. Breast-feeding was permitted in both studies.
Efficacy of ROTARIX against any grade of severity of rotavirus gastroenteritis through one rotavirus season was 87.1% (95% CI: 79.6, 92.1); TVC efficacy was 87.3% (95% CI: 80.3, 92.0). Efficacy against severe rotavirus gastroenteritis through one rotavirus season was 95.8% (95% CI: 89.6, 98.7); TVC efficacy was 96.0% (95% CI: 90.2, 98.8) (Table 4). The protective effect of ROTARIX against any grade of severity of rotavirus gastroenteritis observed immediately following dose 1 administration and prior to dose 2 was 89.8% (95% CI: 8.9, 99.8).
Efficacy of ROTARIX in reducing hospitalizations for rotavirus gastroenteritis through one rotavirus season was 100% (95% CI: 81.8, 100); TVC efficacy was 100% (95% CI: 81.7, 100) (Table 4). ROTARIX reduced hospitalizations for all cause gastroenteritis regardless of presumed etiology by 74.7% (95% CI: 45.5, 88.9).
A randomized, double-blind, placebo-controlled study was conducted in 11 countries in Latin America and Finland. A total of 63,225 infants received ROTARIX (n = 31,673) or placebo (n = 31,552). An efficacy subset of these infants consisting of 20,169 infants from Latin America received ROTARIX (n = 10,159) or placebo (n = 10,010). Vaccine or placebo was given to healthy infants as a 2-dose series with the first dose administered orally from 6 through 13 weeks of age followed by one additional dose administered at least 4 weeks after the first dose. The 2-dose series was completed by the age of 24 weeks of age. For both vaccination groups, the racial distribution of the efficacy subset was as follows: Hispanic 85.8%, white 7.9%, black 1.1%, and other 5.2%; 51% were male.
Efficacy of ROTARIX against severe rotavirus gastroenteritis through one year was 84.7% (95% CI: 71.7, 92.4); TVC efficacy was 81.1% (95% CI: 68.5, 89.3) (Table 5).
Efficacy of ROTARIX in reducing hospitalizations for rotavirus gastroenteritis through one year was 85.0% (95% CI: 69.6, 93.5); TVC efficacy was 80.8% (95% CI: 65.7, 90.0).
Parents or guardians should be informed by the healthcare provider of the potential benefits and risks of immunization with ROTARIX, and of the importance of completing the immunization series.
The healthcare provider should inform the parents or guardians about the potential for 452 adverse reactions that have been temporally associated with administration of ROTARIX or other vaccines containing similar components.
The parent or guardian should immediately report any signs and/or symptoms of intussusception.
The parent or guardian accompanying the recipient should be instructed to report any adverse events to their healthcare provider.
The parent or guardian should be given the Vaccine Information Statements, which are required by the National Childhood Vaccine Injury Act of 1986 to be given prior to immunization. These materials are available free of charge at the Centers for Disease Control and Prevention (CDC) website (www.cdc.gov/vaccines).
Rotavirus Vaccine Linked to Serious Intestinal Disorder in Infants
Infants who receive the rotavirus vaccine, which protects against a severe diarrheal disease, may have a very small risk of developing a serious intestinal disorder called intussusception, a new study finds.
In the study, researchers examined information collected from the administration of 1.2 million doses of RotaTeq, the most common rotavirus vaccine used in the United States, and more than 100,000 doses of Rotarix, another rotavirus vaccine licensed for use in the U.S.
Source: Live Science, 14th January 2014 - http://www.livescience.com/42544-rotavirus-vaccine-side-effect-intussusception.html
Telegraph Reader Remark on Rotavirus Vaccine Shedding
Our youngest son ended up in hospital with dehydration with this lovely bug when he was 3 weeks old, he contracted it from his cousin who was on his first visit from America, mum and dad didn't bother telling us he has just been vaccinated, and so he would be infectious for 21 days.
Other Reader Comments
From above:- "The bug is the main causes of stomach upsets in young children and causes around 140,000 diarrhoea cases a year in under fives"
When my own children were babies, more than 40 years ago, new mothers were carefully taught hygiene techniques to prevent their babies from contracting 'stomach bugs'. A health visitor came round regularly to ensure that everything was carefully sterilised and that nappies were also laundered safely, (no disposables in those days!) Breast feeding also protects young babies by transferring mothers' immunity. I believe that vaccines for common childhood ailments like diarrhoea, should be used sparingly. Vaccines are NOT problem free.
Vaccine the Greater Risk?
Breastfeeding Prevents Rotavirus!
The reason why this vaccine was developed (aside from money) is because children in third world countries without access to clean water and often the prey of baby milk companies who would stop mothers breastfeeding their infants, would develop gastroenteritis and die as a result.
This situation does not occur in developed countries where we have access to clean water, sterilization, and re-hydration sachets.
Bottle fed babies get gastroenteritis more frequently than breastfed ones but at least in first world countries their parents can be sure that the water they use to mix up a feed is clean.
Studies Showing Breast Milk Immunises Against Rotavirus
Human milk mucin inhibits rotavirus replication and prevents experimental gastroenteritis.
Acute gastrointestinal infections due to rotaviruses and other enteric pathogens are major causes of morbidity and mortality in infants and young children throughout the world. Breast-feeding can reduce the rate of serious gastroenteritis in infants; however, the degrees of protection offered against rotavirus infection vary in different populations. The mechanisms associated with milk-mediated protection against viral gastroenteritis have not been fully elucidated. We have isolated a macromolecular component of human milk that inhibits the replication of rotaviruses in tissue culture and prevents the development of gastroenteritis in an animal model system. Purification of the component indicates that the antiviral activity is associated with an acidic fraction (pI = 4.0-4.6), which is free of detectable immunoglobulins. Furthermore, high levels of antiviral activity are associated with an affinity-purified complex of human milk mucin. Deglycosylation of the mucin complex results in the loss of antiviral activity. Further purification indicated that rotavirus specifically binds to the milk mucin complex as well as to the 46-kD glycoprotein component of the complex. Binding to the 46-kD component was substantially reduced after chemical hydrolysis of sialic acid. We have documented that human milk mucin can bind to rotavirus and inhibit viral replication in vitro and in vivo. Variations in milk mucin glycoproteins may be associated with different levels of protection against infection with gastrointestinal pathogens.
Source: J Clin Invest. 1992 November; 90(5): 1984–1991, doi: 10.1172/JCI116078
Prevention of rotavirus-induced diarrhea by preferential secretion of IgA in breast milk via maternal administration of Lactobacillus gasseri SBT2055.
Rotavirus (RV)-induced diarrhea poses a major health problem, particularly to infants. An effective measure to prevent RV infection is to consume breast milk with higher levels of protective IgA. We therefore examined whether Lactobacillus gasseri SBT2055 (LG2055) could augment immunoglobulin (Ig) A levels and reduce the incidence of diarrhea in a mouse model of RV infection.
Female BALB/c mouse dams were fed a diet containing 0.1% heat-treated LG2055 or a control, beginning 4 weeks before mating with male mice and continuing until the experiment ended. One week after mating, female dams were immunized orally with simian RV SA-11. Five days after birth, mouse pups were infected orally with RV and the incidence of diarrhea was determined 4 days later. RV-specific and total IgA were quantified by an enzyme-linked immunosorbent assay.
LG2055-fed dams immunized with RV (LG2055/RV) secreted breast milk that significantly lowered the incidence of RV-induced diarrhea in their pups as compared with dams immunized with RV alone (C/RV). The LG2055/RV dams also produced a significantly greater amount of RV-specific IgA in breast milk obtained from the pups' stomach, but not in feces or Peyer's patch cell cultures. In addition, LG2055 stimulated total IgA production in splenocyte cultures from Toll-like receptor (TLR)-4-knockout mice, but not those from TLR-2-knockouts.
LG2055-fed dams reduced RV infection in their pups and elevated RV-specific IgA levels in breast milk of stomach origin, the possible mechanism of which may be TLR-2 stimulation by LG2055.
Source: J Pediatr Gastroenterol Nutr. 2012 Jul;55(1):66-71.
Enhancement of the circulating antibody secreting cell response in human diarrhea by a human Lactobacillus strain.
Human Lactobacillus sp strain GG (Lactobacillus GG) administered during acute rotavirus diarrhea has been shown to promote clinical recovery. To elucidate the immune mechanisms behind such a favorable outcome, the ELISPOT (solid phase enzyme-linked immunospot) assay of Ig- and specific antibody-secreting cells among circulating lymphocytes was used, giving indirect evidence of the immunologic events in the gut. After rehydration, 39 children with acute rotavirus diarrhea, mean age 16 (SD 6) mo, randomly received either a Lactobacillus GG fermented milk product (study group) or a pasteurized yogurt (placebo group). The duration of diarrhea was significantly shorter in the study group than in the placebo group [mean 1.1 (SD 0.6) versus 2.5 (SD 1.4)d, p = 0.001]. Lactobacillus GG therapy was associated with a significantly enhanced nonspecific humoral response during the acute phase of the infection, reflected in the IgG, IgA, and IgM Ig-secreting cell numbers. At convalescence, 90% of the study group versus 46% of the placebo group had developed an IgA specific antibody-secreting cell response to rotavirus (p = 0.006). The results indicate that Lactobacillus GG promotes recovery from rotavirus diarrhea via augmentation of the local immune defense. Furthermore, specific IgA response to rotavirus is endorsed, which is possibly relevant in protection against reinfections.
Source: Pediatr Res. 1992 Aug;32(2):141-4.
Human-Milk Glycans That Inhibit Pathogen Binding Protect Breast-feeding Infants against Infectious Diarrhea
Breast-feeding is a highly effective strategy for preventing morbidity and mortality in infancy. The human-milk glycans, which include oligosaccharides in their free and conjugated forms, constitute a major and an innate immunologic mechanism by which human milk protects breast-fed infants against infections. The glycans found in human milk function as soluble receptors that inhibit pathogens from adhering to their target receptors on the mucosal surface of the host gastrointestinal tract. The α1,2-linked fucosylated glycans, which require the secretor gene for expression in human milk, are the dominant glycan structure found in the milk of secretor mothers, who constitute the majority (∼80%) of mothers worldwide. In vitro and in vivo binding studies have demonstrated that α1,2-linked fucosylated glycans inhibit binding by campylobacter, stable toxin of enterotoxigenic Escherichia coli, and major strains of caliciviruses to their target host cell receptors. Consistent with these findings, recently published epidemiologic data demonstrate that higher relative concentrations of α1,2-linked fucosylated glycans in human milk are associated with protection of breast-fed infants against diarrhea caused by campylobacter, caliciviruses, and stable toxin of enterotoxigenic E. coli, and moderate-to-severe diarrhea of all causes. These novel data open the potential for translational research to develop the human-milk glycans as a new class of antimicrobial agents that prevent infection by acting as pathogen anti-adhesion agents.
Source: J. Nutr. May 1, 2005 vol. 135 no. 5 1304-1307.
Full Text Here: http://jn.nutrition.org/content/135/5/1304.full
Cord blood and breast-milk antibodies in neonatal rotavirus infection
Studies were carried out during an outbreak of rotavirus type 2 infection in a neonatal nursery to determine the protective role of antibodies in cord blood and breast milk. The range, distribution, and geometric mean titres of rotavirus-specific antibody in the cord blood were similar among rotavirus-positive and rotavirus-negative neonates, and the amount of virus excreted did not correlate with antibody levels. Despite the protective effect of breast feeding, the pattern of rotavirus-specific IgA and IgG antibodies in the expressed breast milk of mothers of babies who were rotavirus excreters and non-excreters was similar. Nevertheless, a higher proportion of expressed breast milk samples contained rotavirus-specific IgA group 2 (92%) and type 2 (97%) specific antibodies than type I (67%) antibodies, and the geometric mean titres of group 2 and type 2 specific antibodies were tenfold higher than type I antibodies. Among breast-fed babies who excreted rotavirus there was no correlation between type 2 rotavirus-specific IgA antibodies in expressed breast milk and the amount of neonatal virus excretion. These studies suggest that factors other than the rotavirus antibodies in expressed breast milk are of importance in preventing rotavirus infection in newborn infants.
Source: Br Med J. 1980 March 22; 280(6217): 828–830. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1600947/
Local production of rotavirus specific IgA in breast tissue and transfer to neonates
Rotavirus specific IgA, secretory component, and IgG were measured by enzyme linked immunosorbent assay in 20 pairs of mothers and babies to estimate antibody transfer from the mother, particularly from breast milk to neonatal faeces. Colostrum contained high titres of specific IgA and secretory component, which decreased gradually. Faeces after breast feeding for three days showed detectable titres of IgA and secretory component, with further increases by seven days. There was a positive correlation between titres of secretory component in breast milk and in faeces. To clarify the mechanism of high anti-rotavirus activity in breast milk, ratios of rotavirus specific IgA in maternal serum samples to breast milk were calculated and compared with those that were herpes simplex virus specific. Significantly higher concentrations were obtained for the herpes simplex virus specific samples, indicating that anti-rotavirus IgA is selectively produced in breast tissue.
Source: Arch Dis Child. 1987 Apr;62(4):401-5. http://www.ncbi.nlm.nih.gov/pubmed/3036019
Rotavirus antibodies in the mother and her breast-fed infant
The transfer of rotavirus antibodies from 25 healthy mothers to their breast-fed infants was investigated during the period of lactation (mean, 3.9 months; range, 1-9 months). Furthermore, the destiny of these antibodies in the infants' gastrointestinal tract and serum was examined. Rotavirus-specific immunoglobulins were analyzed by the ELISA (enzyme-linked immunosorbent assay) technique. All the mothers had rotavirus IgA and IgG in serum. About 80% of the mothers had low concentrations of rotavirus ScIg (i.e., antirotavirus immunoglobulin containing secretory component) in serum at the beginning of the lactation period declining to about 45% at the end of the period. From a few days after delivery to about 2 weeks later, the concentrations of rotavirus IgA and ScIg in milk declined. Thereafter, they remained unchanged. There was a positive correlation among the concentrations of rotavirus IgA in serum and rotavirus IgA as well as ScIg in milk. Rotavirus IgG in the infants' serum correlated with that of the mothers. Few samples of the infants' duodenal fluid contained rotavirus IgA or ScIg. On the other hand, about 80% of the infants' fecal samples contained rotavirus ScIg and IgA. Rotavirus IgA and ScIg disappeared from the infants' feces after cessation of lactation. Hence, it may be concluded that infants receive rotavirus IgG through the placenta, and rotavirus ScIg and IgA in constant amounts via milk throughout the period of lactation. The small intestine is flushed with rotavirus ScIg and IgA at each breast-meal, and these antibodies survive proteolysis in the gut. A possible protectional effect of rotavirus ScIg or IgA requires frequent breast-meals, and the effect is limited to the period of lactation.
Source: J Pediatr Gastroenterol Nutr. 1985 Jun;4(3):414-20. http://www.ncbi.nlm.nih.gov/pubmed/2991489
Transfer of antibody via mother's milk
Differing from humans, IgG from breast milk in many animal species (rodents, bovines, cats, ferrets, etc.) are transported across the intestinal epithelium into the neonatal circulation. This transport is located at the duodenal and jejunal level where enterocytes express a surface membrane receptor able to bind Fc of IgG and to facilitate transcytosis of these immunoglobulins. Fcgamma-R, which is very similar to the placenta receptor responsible for active transplacental transfer of IgG in humans, binds IgG but not other isotypes. Maternal milk antibodies represent an important part of circulating IgG in these animals, as they are involved in the negative feedback of endogenous IgG synthesis. This phenomenon stops abruptly as soon as weaning takes place. Neonatal calves that have a defect in such transfer of maternal immunoglobulins are at high risk of systemic infectious diseases. In humans, in whom gut closure occurs precociously, breast milk antibodies do not enter neonatal/infant circulation. A large part of immunoglobulins excreted in milk are IgA that protect mainly against enteric infections. The specificity of maternal milk IgA is driven by an entero-mammary cell circulation. Human milk also contains anti-idiotypic antibodies capable of enhancing infant antibody response. Maternal milk antibodies coat infant mucosal surfaces and some have a clear protective role. This has been studied extensively in infectious disease models such as rotavirus, E. coli, poliovirus, and retroviruses. In the rotavirus model, antirotaviral IgA can be detected in stools of breast-fed but not bottle-fed neonates. In a large cohort of lactating women infected with HIV-1 in Rwanda, anti-HIV milk antibodies of the IgG isotype were more frequently detected followed by secretory IgM. Surprisingly, anti-HIV-1 SIgA were less frequently found. The presence of milk SIgA at 15 days as well as the persistence of a SIgM response during the whole lactation period was associated with lower risk of HIV transmission from the mother to the infant. Recently, HIV-1 antibodies from maternal milk have been shown to block transcytosis in vitro in a monolayer enterocyte model. Among these antibodies, those directed against the ELDKWA epitope had higher neutralising activity than serum antibodies. In humans, milk excreted antibodies play a major role in protecting infants from infection by pathogens having a mucosal portal of entry.
Source: Vaccine. 2003 Jul 28;21(24):3374-6. http://www.ncbi.nlm.nih.gov/pubmed/12850343