Rotavirus

Before the introduction of the vaccine, few people have heard of rotavirus infection, despite the fact that almost all children got infected with it.

Rotavirus was discovered in 1972, and was called so due to its similarity to a wheel. The virus is the most common cause of gastroenteritis in infants and children. It is transmitted by fecal-oral route.
The first infection after 3 months of age is usually the most severe. It can be asymptomatic, can cause mild diarrhea, or it can cause severe diarrhea with fever and vomiting. The symptoms usually resolve in 3-7 days. Similar symptoms can also be caused by other pathogens, not just rotavirus, so a laboratory testing is required for confirmation.
In temperate climates, the disease is more common during fall and winter periods. There are currently two oral rotavirus vaccines: RotaTeq and Rotarix. RotaTeq is given in 3 doses (at 2, 4 and 6 months old), and Rotarix is given in two doses (at 2 and 4 months old). The first dose should not be given later than at 14 weeks old, and the last dose should not be given later than at 8 months old.
Vaccines are 74%-90% effective for the serotypes they contain. Duration of immunity is unknown.
Since effectiveness and safety of more than one dose had not been studied, it is not recommended to give the infant another dose if the infant either spits out or regurgitates it.
In clinical studies, those who received RotaTeq vaccines registered more cases of diarrhea and vomiting during the first week after vaccination, than those who got placebo. During 42 days after vaccination, diarrhea, vomiting, otitis media, nasopharyngitis and bronchospasm occurred more in those vaccinated.
In those vaccinated with Rotarix, cough and runny nose were observed more often during 7 days after vaccination, and irritability and flatulence occurred more often during the month following vaccination, as compared to the ‘placebo’ group.

The probability of diarrhea upon primary rotavirus infection is 47%. With subsequent infections the probability of diarrhea decreases. Having had rotavirus diarrhea decreases the risk of diarrhea upon repeat infection by 77%, and the risk or severe diarrhea by 87%. Two/three rotavirus diarrheas decrease the risk of subsequent infection by 83%/92%.
Having had asymptomatic infection decreases the risk of subsequent infection by 38%.
Having had two infections (symptomatic or asymptomatic) gives 100% protection from severe diarrhea.
Short breastfeeding period increases the risk of rotavirus infection.

Repeat infection with rotavirus is possible, but it either has mild symptoms or is asymptomatic.
There are 7 serotype groups of the virus (A-G). Group A is divided into G1-G14, P1-P11 and other serotypes. People usually get infected by G1-G4 serotypes of group A, and less commonly by groups B and C.
Infant infections are usually asymptomatic. Subsequently, they get infected with rotavirus less often and have milder symptoms than those who did not get infected after birth. Infant infection, both symptomatic and asymptomatic, provides protection for 2 years. After the early childhood period, symptomatic infection rarely happens.
Exclusive breastfeeding during the first year of life decreases the risk of infection.

Development of rotavirus vaccine began in the 90s, so the CDC began to wonder, who many kids die from it. They conducted the following studies on this question:

Death from diarrhea (for any reason) makes up 2% of all post-neonatal mortality rates. In 1983, an average of 500 children died of diarrhea in USA in a year, 50% of them died in hospitals. Diarrheal death rate decreases drastically with age – it is twice as high for infants at the age of 1-3 months, as at the age of 4-6 moths, and 10 times higher than for 12-months-olds.
Risk of diarrheal death is 4 times higher for black people (and in some states 10 times higher) than for white people; 5 times higher for infants whose mothers are younger than 17 years old; twice as high for those, whose parents are unmarried; 3 times higher for those, whose parents have not graduated from high school.
Diarrheal mortality rate is higher in winter than in summer, and it is believed that the rotavirus is responsible for that. It is estimated that 70-80 children die each year from rotavirus.

Diarrheal death rate in the USA decreased by 75% (79% among infants) and stabilized between 1968 and 1985. 300 people (240 of them children) died of diarrhea each year between 1985 and 1991. Mortality rate among children was 1:17,000. From 1985, half of the children died at the age under 1.5 months (that is, before the vaccination age).
Here’s a graph of diarrheal mortality rate from 1968 to 1991.
Every winter it is possible to observe death peaks that disappear in the mid-1980s, and only small peaks remain in the group of 4-23 month old children. As rotavirus is affected almost and exclusively in the winter, the authors believe that those peaks are deaths from rotavirus.
The authors conclude that a vaccine against rotavirus will have a measurable but small impact on mortality from diarrhea.

It is estimated that 873 thousand people die from rotavirus each year around the world. However, there was no information on mortality rate of rotavirus in developed countries, and so in 1985 IOM concluded that this vaccine is not a priority for the USA. However, they used one prospective study as a basis, even though other studies determined that one third of children hospitalized with diarrhea had rotavirus infection.
Since not a single child in the USA died with a rotavirus diarrhea diagnosis, many pediatricians believed that rotavirus is never severe or lethal. However, mortality data analysis (in the previous studies) provided convincing, albeit circumstantial proof, that rotavirus can be lethal.
On the basis of two previous studies, the authors estimate that 55,000 children are hospitalized due to rotavirus each year, and 20 children die, i.e. 1 in every 200,000. They believe that these children also had some other disease, or they were premature, for example.
The authors conclude that less than 40 children each year die of rotavirus, although they never explain how they came up with the number ‘40’, since they only counted 20 in the body of article.
CDC claims that 20-60 children die of rotavirus each year, but they do not explain where they got ‘60’ from, since their own studies only got 20.

- The first rotavirus vaccine (Rotashield) was licensed in 1998 and contained 4 strains. It was withdrawn in 1999, because it was associated with intussusception. Intussusception is when part of the intestine folds onto itself, like a telescope.
- The public does not want to put up with even a slight risk of serious side effects, not even as low as 1 in 10,000.
- In 1998, Rotarix (GSK) vaccine was licensed. It contains one strain. The isolated strain from an infected child was attenuated by 33 sequential passages in kidney cells of African green monkeys. The vaccine strain multiplies well in the human intestines.
- In 1996, RotaTeq (Merck) vaccine was licensed. It contains 5 strains. (Our friend, Paul Offit, owns four patents for this vaccine.)
Unlike the other live vaccines, RotaTeq is not an attenuated, but a reassortant vaccine.
The rotavirus genome consists of 11 RNA segments. In the RotaTeq vaccine strains, some human rotavirus segments are replaced with bovine rotavirus. Such vaccines, in which some virus RNA segments were replaced by segments of animal virus strains, are called reassortant vaccines. RotaTeq is a pentavalent vaccine. The four most common serotypes (G1-G4) are combined with bovine serotype P. The fifth strain consists of bovine serotype G combined with human serotype P. Three vaccine strains are reassortant of one human and ten bovine segments. The other two are reassortant of two human and nine bovine segments. Such virus does not multiply well in the intestines, which is why RotaTeq has 100 times more virus particles than Rotarix.
The first vaccine (Rotashield) was also reassortant, but it used segments of monkey virus.
The vaccine contains polysorbate 80 and fetal bovine serum.
In clinical trials of both vaccines, the same vaccine, but with no virus, was used as a placebo. [1], [2].

(Shedding)
- During the clinical trials of Rotashield, vaccine strains were detected in the stool of those who received placebo a year after the beginning of the trial, and were no longer detected 100 days after the end of the trials, which indicates the establishment of “common reservoir.”
- Rotarix clinical trials found that about 50%-80% of infants secrete the virus after the first dose. A Singapore study found that approximately 80% of infants secrete the virus on the 7th day after vaccination, and 20% continue to secrete it a month after vaccination. A study in Dominican Republic revealed that 19% of unvaccinated twins got infected with a vaccine strain by their vaccinated brothers.
- 14% of infants secrete the virus after the first dose of RotaTeq. It is reported here, that 21% of infants secrete the virus after RotaTeq, and here, that it’s 87%.
It is reported [here=https://www.ncbi.nlm.nih.gov/pubmed/21856359/], that 53% of premature infants secrete the virus after RotaTeq.
- It is believed that secreting of the vaccine virus and its spread is an undesirable side effect, but it also has a potential benefit. Infecting the unvaccinated will make them develop immunity, the same way as it happens with the polio vaccine. Especially significant benefit will be achieved in poor countries, where the vaccination coverage is low, mortality rate is high, and immunodeficient people are few. Of course in developed countries, where mortality rate is low, and immunodeficient people are many, and most people prefer to avoid risk, secreting vaccine strains might be considered as undesirable effect.
- 1 gram of stool of an infected child contains 100 billions of virus particles. Only 10 particles are sufficient to get infected. This is why adults, who change babies’ diapers, are at risk of getting infected. Immunodeficient people should not change diapers of a vaccinated baby, especially within 2 weeks of RotaTeq, and 4 weeks of Rotarix vaccinations.

Exclusive breastfeeding decreases the risk of rotavirus infection by 38%. More: [1], [2], [3], [4], [5], [6], [7], [8].
Breast milk of mothers in Sweden had much more rotavirus antibodies in the spring than in the fall.
The level of zinc in the blood correlates with protection against rotavirus. Late vaccination (at 17 weeks old) is more effective than vaccination at 10 weeks old.

In poor countries, rotavirus vaccines are less immunogenic and less effective than in developed countries. If Rotarix vaccine causes an immune response in more than 90% of infants in Finland, in South America it is only 70%, and in South Africa, Malawi, Bangladesh and India it is 40-60%. Other oral vaccines (polio and cholera) are also less effective in poor countries.
It is still unclears why this happens, but one of the possible explanations is that mothers in these countries are more likely to breastfeed their babies during vaccination. Also, mothers in poor countries have natural immunity to rotavirus more often, which results in more antibodies in breast milk, and IgG antibodies, which are transmitted through the placenta.
The authors took samples of breast milk from India, Vietnam, South Korea and the USA, and checked whether it has inhibitory effect on rotavirus.
It turned out that breast milk samples from India had the most rotavirus antibodies, breast milk from Vietnam and South Korea had less antibodies, and breast milk from the USA had the least.
The authors recommend developing parenteral rotavirus vaccines, and investigating whether limiting breastfeeding at the time of vaccination will affect its immunogenicity. More: [1].
It is reported here, that abstaining from breastfeeding during one hour before and after the vaccination does not affect the immunogenicity of the vaccine. More: [1], [2].

Cochrane systematic review. In developed countries, vaccination reduces the risk of diarrhea by 40%, and the risk of severe rotavirus diarrhea by 86%.
It was not found that vaccination reduces mortality rate.
Serious adverse events (SAE) were reported in 4.6% of vaccinated with Rotarix and 2.4% of vaccinated with RotaTeq. Similar number of SAE was reported in the ‘placebo’ group.

Rotavirus vaccination in the USA will prevent 63% of all rotavirus cases, and 79% of all serious cases, thus preventing 13 deaths and 44,000 hospitalizations per year.
If the price of the vaccine dose is more than $12, vaccination will not be economically feasible, and at the price over $42, it will not be justifiable from the societal point of view either. Today, RotaTeq costs $69-$83 per dose, and Rotarix is $91-$110 per dose.

In 15 months after the introduction of the vaccination in Brazil, G2P(4) rotavirus strain has replaced all other strains, even though it was only seen in 19%-30% of cases prior to the introduction of vaccination. Effectiveness of the vaccine (Rotarix) against this strain was 77% among children of 6-11 months of age, and -24% (negative) among children over 12 months of age. More: [1], [2].
It is reported here, that after the introduction of vaccination in Brazil, regular rotavirus strains got replaced with the new GP12(8) strain. Strain replacement also took place in Paraguay==https://www.ncbi.nlm.nih.gov/pubmed/20213281] and in Argentina.

Effectiveness of the vaccine (Rotarix) among 6-11 months old children in Columbia was 79%, and 63% against severe cases of diarrhea, and 67% against very severe cases.
Effectiveness among children over 12 months of age was -40%, and -6% against severe cases, and -156% against very severe cases (negative effectiveness).
Overall effectiveness of the vaccine for all ages was -2%, and -54% against severe cases, and -114% against very severe cases (negative effectiveness).
In central Australia, effectiveness of two doses of Rotarix was 19%, and effectiveness of one dose was null.
It is reported here, that there is no correlation between the number of antibodies developed and clinical effectiveness of the vaccine.

Rotarix effectiveness against rotavirus diarrhea in a Bangladeshi study was 41%. Its effectiveness against all types of diarrhea turned out to be negative (-2.2%).

The authors tested stool samples of 1,106 infants suffering from gastroenteritis, and found group A rotavirus in 25% of them. 13% of the detected strains were vaccine strains.

Since the rotavirus genome consists of separate segments, when two different strains of the virus infect the same cell, they can exchange segments and create a new strain. This is the same reassortment, which happens on its own.
A case of gastroenteritis in a 7-year-old girl is reported here. A rotavirus strain was isolated from her stool sample. The strain was reassortant of two other human-bovine strains from the RotaTeq vaccine. However, the girl has not been vaccinated against rotavirus. Moreover, she has not been in contact with anyone who has been vaccinated. Her two brothers also had similar gastroenteritis symptoms, and they also have not been vaccinated or in contact with anyone who has been.
The isolated reassortant strain of the virus turned out to be stable and very contagious. The authors believe that this new virus is most likely circulating in the population. Reassortant viruses have previously been isolated, but only in those recently vaccinated with RotaTeq: [1], [2], [3].
Cases of detecting new virus strains from reassortment of wild virus with Rotarix vaccine strain are reported here.
It is reported here, that 17% of children secreted the virus after vaccination, and 37% of them secreted a double reassortant virus. Some children secreted the virus for a long time after the vaccination, form 9 to 84 days after the last dose.

The authors analyzed the rotavirus genome of the vaccinated children suffering from gastroenteritis in Nicaragua, and found new strains of the virus, which formed due to reassortment between the wild strain and the RotaTeq vaccine strains.

Among children who had diarrhea within two weeks of vaccination, 21% had been infected with the vaccine strain. 37% of the isolated vaccine strains were reassortant from two RotaTeq strains.

Frequent rotavirus infections are associated with an increased risk of celiac disease.
HLA-DQ2 (a gene, whose expression is associated with celiac disease) is detected in 20%-30% of healthy white people. Nonetheless, less than 1% of population gets celiac disease. More: [1].

Type 1 diabetes incidence among children under 18 years of age in Israel increased by 6% per annum between 2000 and 2008. Among children under 5 years of age, it increased by 104% in 6 years. The authors suggested that viral infections could be one of the factors in the disease, which mean that rotavirus vaccination might reduce the risk of diabetes. It turned out, however, that there were 7.4 times more vaccinated than unvaccinated among type 1 diabetes patients.

After the introduction of rotavirus vaccination in France, 508 side effects have been registered (201 of them serious), and 47 cases of intussusception. 2 infants died of intussusception, and another one died of necrotizing enterocolitis. In the five years preceding the vaccination, only one lethal case of intussusception has been reported. Therefore, rotavirus vaccine has not been included into the national immunization schedule and is not financed by the government.
Clinical studies of the vaccine did not determine that the vaccine reduced overall mortality neither in developed, nor in developing countries.

Merck reports that in clinical trials of RotaTeq, the risk of epileptic seizures in vaccinated was twice as high as compared to the ‘placebo’ group. Kawasaki syndrome was registered in 5 patients vaccinated with RotaTeq and one patient from the ‘placebo’ group. Among the premature babies, adverse events were registered in 5.5% of vaccinated patients and 5.8% of ‘placebo’ group.
GSK reports that in clinical trial of Rotarix, mortality rate was 0.19% among the vaccinated patients, and 0.15% in the ‘placebo’ group. The risk of Kawasaki syndrome was increased by 71% in those vaccinated.

In the largest clinical trial of Rotarix (63,000 children), 2.7 times more deaths from pneumonia were registered in the vaccinated group, as compared to the ‘placebo’ group. The FDA believes that this is most likely a coincidence. It is possible that the vaccine increases the risk of Kawasaki syndrome. More [1], [2].

In 2010, a group of independent researchers accidentally found porcine circovirus (PCV1) in the Rotarix vaccine, and the FDA decided to temporarily suspend vaccination. At first, FDA stated that RotaTeq did not have porcine virus, but two months later, it turned out that RotaTeq contains two kinds of porcine virus, PCV1 and PCV2. The FDA assembled a committee, which concluded that these viruses are most likely harmless to humans, and that the benefits of vaccination outweigh the hypothetical harm. The committee also recommended that manufacturers develop vaccines without porcine viruses. One week after detecting the viruses in RotaTeq, the FDA recommended pediatricians to resume vaccination with both vaccines. It has been 8 year, but the manufacturers are in no hurry to develop vaccines without the porcine viruses.
In this study, the authors wanted to determine whether porcine viruses multiply in human intestine. They did not find porcine viruses, but they did detect a baboon endogenous M7 virus in the RotaTeq vaccine, which probably got there from kidney cells of African green monkeys, in which the vaccine virus is produced.
The Chinese vaccine uses the sheep rotavirus strain, which is produced in the kidney cells of cows, and the porcine virus was not detected in the vaccines.
It is reported here, that the PCV2 porcine virus, which has been known for 40 years and was harmless, has suddenly mutated and spread throughout the world, causing disease in young pigs and becoming deadly to the pigs. More: [1]

RotaTeq vaccine is associated with a nine-fold risk of intussusception (1 in every 65,000). This is significantly lower, than the risk from the withdrawn Rotashield vaccine (1-2/10,000).

Rotarix increases the risk of intussusception during the week after the first dose of the vaccine by 8.4 times.

In Australia, Rotarix increased the risk of intussusception during the week after vaccination by 6.8 times, and RotaTeq – by 9.9 times.
In Mexico, Rotarix increased the risk in intussusception by 6.5 times.

Meta-analysis of 11 studies. The first dose of the rotavirus vaccine increases the risk intussusception by 3.5-8.5 times.
Other studies proving the increased risk of intussusception after vaccination: [1], [2], [3], [4], [5].
It is reported here, that the number of intussusception cases in the studies is most likely underestimated by 44%.

Despite the obvious benefits of vaccination, no vaccine is completely safe. Post-clinical studies have shown that recently licensed rotavirus vaccine increases the risk of intussusception. However, it is unknown what risk would be acceptable to the parents, and how much they would be willing to pay for this vaccine.
To reach the 50% vaccination coverage, the parents are ready to allow 2,897 cases of intussusception per year, which would cause 579 surgeries and 17 additional lethal cases. And to achieve 90% coverage, the parents are ready to allow no more than 1,794 cases of intussusception per year, including 359 surgeries and 11 deaths due to vaccine.
Without rotavirus vaccine 20 children die.
The lower the parents’ income, the higher the risk they are willing to accept.
The parents are willing to pay $110 for three doses of risk-free vaccine, but only $36 for three doses or risky vaccine.
Other studies already determined that parents prefer death from disease, rather than from vaccine, and this study confirms this fact.

Both twins received the Rotarix vaccine, and one week later one of them developed intussusception symptoms, and was urgently taken into surgery. A few hours after the surgery, the other twin started to experience the same symptoms, and he also underwent surgery, but not as urgently.

Two-months-old girl was vaccinated with Rotarix in Japan, and in 10 days her two-years-old sister was hospitalized with severe gastroenteritis. It turned out that her sister infected her with a mutated vaccine strain of the virus.
A similar case with a RotaTeq vaccine in the USA is reported here. Vaccinated infant infected his brother 10 days post-vaccination with a rotavirus strain that was reassortant of two vaccine strains.

Immunodeficient infants can suffer from severe gastroenteritis for a long time after vaccination. However, at the age of two months, when the vaccination is given, it is still unknown whether the infant is immunodeficient or not. The authors propose to check children for congenital genetic defects prior to vaccination. More: [1].

In 10 years, between 2007 and 2016, 514 deaths and 230 disability cases due to rotavirus vaccine, have been registered with VAERS. Prior to the introduction of vaccination, 20 deaths per year were registered, i.e. 1:200,000 (and even those might not all have been due to rotavirus).
Taking into account that only 1%-10% of all cases get registered with VAERS, the probability of dying due to the vaccine is 25-250 higher, than the probability of dying due to rotavirus.