Haemophilus influenzae

Haemophilus influenzae, pneumococcus and meningococcus are the three main types of bacteria that can cause meningitis and other invasive diseases. Bacterial meningitis, unlike viral meningitis, can be very dangerous.

Haemophilus influenzae is a bacterium, which was initially believed to be the cause of influenza (thus the name was derived).
The bacterium forms a polysaccharide capsule around itself. There are six serotypes of H. influenzae (a-f) by capsule type. The vaccine exists only for serotype b, which caused 95% of H. influenzae infections in pre-vaccination era. There are also noncapsulated strains.
In pre-vaccination era, one in every 200 children had H. influenzae. Hib could be found in the nasopharynx of 0.5%-3% of healthy infants.
Almost all cases of H. influenzae occurred in children under 5 years of age, and two thirds occurred in children under 18 months of age.
Invasive infection can cause meningitis, epiglottitis, pneumonia, arthritis and cellulitis. Mortality rate of meningitis is 3%-6%, while neurologic disorders remain in 15%-30% of survivors. The exact way the bacteria invades the bloodstream is unknown.
In 2010-2011, 33% of Hib patients were under 6 months old (that is, they have not been fully vaccinated yet). Among the remaining Hib cases, 36% occurred in fully vaccinated patients. The rest were unvaccinated, or vaccinated with fewer than 3 doses, or vaccinated with an unknown number of doses.
Risk factors of Hib disease include crowding, low socioeconomic levels, low parental education levels, chemotherapy, etc. Latin Americans and Native Americas get sick more often than white people.
Breastfeeding provides a protective effect for the first 6 months. In the pre-vaccine era, most children developed natural immunity by the age of 5-6 years.
The first Hib vaccine (polysaccharide) was used from 1985 till 1988, but it was ineffective in children younger than 18 months. In older children the efficacy varied from 88% to -69%.
A conjugate vaccine has been used since 1988, and is usually given at 2, 4, 6 and 12 months of age.
There is a monovalent Hib vaccine, but it is more commonly used as part of a penta- and hexavalent vaccines (with diphtheria, tetanus, pertussis, polio and hepatitis B).

Conjugate vaccines are a special category of vaccines. The H. influenzae bacterium capsule is a carbohydrate (polysaccharide). Creating an effective polysaccharide vaccine turned out to be impossible, since the immune system does not really want to develop carbohydrate antibodies for some reason. To solve this problem, protein has been attached to the polysaccharide (diphtheria or tetanus toxoids are usually used for that), and thus, the immune system develops carbohydrate antibodies together with the protein antibodies.
Other conjugate vaccines are pneumococcal and meningococcal vaccines.

The authors analyzed 974 healthy unvaccinated children in Cuba, and found that by the age of 4-5 years, 99.7% of them had natural Hib immunity. Natural Hib immunity was also found in Finland (79%) and in India (80%).
Therefore, the WHO recommends introducing this vaccine into the national immunization schedule only in countries that can afford it financially, without taking resources from other important vaccines.
Natural immunity to Hia was found in indigenous in Canada. More: [1].

Hib incidence in the USA has increased five fold between the 1940s and the 1960s.

Before the introduction of vaccination, Hib incidence was 30/100,000 among white, and 600/100,000 among indigenous people in Alaska. The incidence in the USA increased by 4 times between 1940 and 1970. The same happened in Scotland and Sweden.
Breastfeeding has a protective effect from Hib meningitis, and it lasts 5-10 years.
A short breastfeeding period (less than 13 weeks) increases the risk of Hib by 3.8 times. Children that are not usually healthy get infected 4.5 times more often.
Breast milk has an inhibitory effect on the attachment of bacteria to the mucous membrane of the nasopharynx.
The graph shows that a decrease in the number of breastfed babies is followed by an increase in the Hib incidence, and when the number of breastfed babied increased again – Hib incidence decreased.

Among children over 1 year of age, short breastfeeding period is associated with a 8-fold increase in the risk of Hib. Each additional week of breastfeeding decreases the risk of Hib by 5%. The protective effect of breastfeeding begins from 13 weeks of exclusive breastfeeding, and lasts for months and years.

Attending daycare is associated with a 5-fold increase in the risk of Hib. Previous hospitalizations – with 90% increase in the risk. Breastfeeding for over 6 months decreases the risk by 53%.

Passive smoking is associated with a 40% increase in the risk of Hib. Daycare – with 3-fold increase in the risk. Breastfeeding decreases the risk by 50%. African Americans got infected 4 times more often.

Breastfeeding for more than a month is associated with a 62% decrease in the risk of Hib meningitis. Breastfeeding for more than 9 months – with 88% decrease in the risk. Daycare – with 2.6-4.7 times increase in the risk.

Among children under the age of 6 months, exclusive breastfeeding is associated with a 90% decrease in the risk of Hib. Attending daycare is associated with a 2-6 fold increase in the risk. The larger are the groups at daycare, the higher is the risk.

Among children infected with Hib, those who were breastfed longer had higher levels of antibodies.

Breastfed children developed significantly more antibodies after the vaccine than children that were given formula.

Analysis of all the Hib cases in Los Angeles in 1988-9 (8.7 million population, 750 thousand of them – children under the age of 5 years). 88 cases were registered among children during the year. Mortality rate was 4.5%.
The risk of Hib in children living in homes with more than two smokers was 6 times higher.
Six or more people living in one hearth is associated with a 3.7-fold increase in the risk of Hib. African Americans get infected 3.5 times more often. Chronic illness and low income also increase the risk.
Vaccination and breastfeeding decrease the risk of Hib (for white people). Vaccination with polysaccharide vaccine increases the risk of Hib.
Another study found that a smoking parent increases the risk of Hib by 2.4 times.

Before the introduction of vaccination, Alaskan Inuits got infected with Hib 10 times more often than the rest of the USA population.
Australian native people, Native American, Inuits and Africans in Gambia and Somalia got infected 3-4 times more often than Americans, and 10 times more often than Europeans.

Polysaccharide Hib vaccine was licensed in the USA in 1985. A clinical trial in Finland found that the vaccine is ineffective in children under the age of 2 years, and is 80% effective for ages 2-3 years. Before the licensing, the only study in the USA of 16,000 children did not find the vaccine effective. The vaccine was thus licensed on the basis of the Finnish study, only for children over 2 years of age (even though most cases occurred in children under 1 year of age). Once the vaccine got licensed, conducting a randomized study turned out to be impossible. However, since Hib is a rare disease, conducting this kind of study is difficult anyway, as it requires many participants.
An observational study in Minnesota found that the effectiveness of this vaccine is negative, and it increases the risk of disease by 58%.
Other studies have found that the vaccine increases the risk of disease in the first week after vaccination. Subsequently, the IOM also determined that polysaccharide Hib vaccine increases the risk of infection.

Children, who received Hib vaccine in infancy, had significantly less antibodies than children vaccinated at the age over 1 year.

The conjugate vaccine is quite effective against serotype B, but same as in the case with HPV, serotype B strains simply get replaced by other strains and other bacteria. The next chapter will show that the decrease in the Hib incidence caused an increase in the pneumococcus incidence. Thus, vaccination against pneumococcus was introduced in 2000, which, in turn, increased the incidence of Hib and streptococcus.

Hib incidence in Manitoba (Canada) decreased due to vaccination, but then it began to increase again, and has already reached the pre-vaccine level.
Previously, only 10% of patients were over 10 years old, and now there are 56%. Similar changes in epidemiology are also observed in the USA.
The authors compared their research data to the official incidence data, and found that only 1 in 17 Hib cases between 2000-2004 was officially registered. They conclude that Hib incidence rate is significantly underestimated, and that the incidence of infection with other strains of H. influenzae bacteria is, most likely, also underestimated.

Vaccination decreased the Hib incidence in Ontario (Canada) by 57%, but the incidence of serotype f increased by 2.4 times, and the incidence of noncapsulated strains increased by 3 times. Hib incidence decreased by 7% annually in children under the age of 5 years, and the incidence of noncapsulated strains increased by 7% annually in children of 5-19 years of age. Overall, the incidence of H. influenzae has not changed much, but the incidence of meningitis has decreased and the incidence of sepsis has increased.
The noncapsulated strains colonize the upper respiratory tracts in 65% of children.

Hib vaccination was introduced in England in 1992, after which the incidence decreased sharply, but has been increasing again since 1999.
443 Hib cases were registered between 1993 and 2001. 82% of them were fully vaccinated. Vaccine effectiveness was 57%.
Effectiveness was lower for children vaccinated in infancy, as compared to those vaccinated at over 1 year of age.
Vaccine effectiveness decreased 2 years after vaccination.
Effectiveness was lower for children born after 2000, as compared to those born earlier.
Effectiveness was lower for children vaccinated with DTap-Hib combination vaccine, as compared to those vaccinated with other vaccines.

One year after introduction of vaccination in Brazil, Hib meningitis incidence decreased by 69% (from 2.62 to 0.81 in 100,000). Hia meningitis (H. influenzae type a) increased 8-fold (from 0.02 to 0.16 in 100,000).
Clinical virulence of Hib and Hia is the same. Hia mortality rate was 23%.

Before the introduction of vaccination, Hib incidence in Alaska was the highest in the world. It decreased sharply due to vaccination, but H. influenzae incidence of other serotypes increased, mostly of serotype A and noncapsulated strains.

After the introduction of vaccination, Hib incidence among adults in England decreased, but the overall incidence of H. influenzae disease increased due to a sharp increase in the incidence of noncapsulated strains, especially among the elderly. Mortality rate was 59%.

Hib incidence among adults in England decreased after the introduction of the vaccine (probably due to herd immunity), reached its low in 1998, but increased back to its pre-vaccine levels by 2003. The level of Hib antibodies in adults decreased after the introduction of vaccination.
The same happened among children. At first, Hib incidence decreased sharply, but then began to increase sharply, despite the high vaccination coverage. The number of cases among children has been doubling each year since 1998, and most of those infected are fully vaccinated.

Vaccination decreased the number of Hib cases in Utah children by 99%, but the incidence of H. influenzae infection among adults increased by 11.5 times between 1998 and 2008. Most cases were of serotype F and noncapsulated strains. Mortality rate was 22%.

Before the introduction of vaccination, 24 Hib cases a year were registered in 1989 in British Columbia (Canada). 45-53 cases in a year were registered between 2008 and 2009. Serotype B incidence decreased, and serotype A incidence increased. Previously, mostly children got infected, but now adults were also getting sick.

The number of Hib cases in Illinois increased by 2.5 times (3.5 times among the elderly) between 1996 and 2004.
The number of cases of infection with noncapsulated Hib strain increased by 657%. In 1996, noncapsulated Hib strain was responsible for 17% of disease cases, whereas in 2004, it was responsible for 71% of the cases already. Mortality rate was 13% (21% among elderly).
Mortality rate for serotype F among the elderly was 11%, and 39% for serotype E.

The incidence of serotype F increased 4-fold between 1989 and 1994, and accounted for 17% of all H. influenzae cases. The mortality rate for this serotype was 30% in adults and 21% in children.

Hib incidence in Netherlands decreased after the introduction of vaccination, and reached a low in 1993, but then started to increase again. Probably because the disappearance of bacteria makes “natural booster” more rare, which leads to weakened immunity, and increased susceptibility to infection.
It could also be because vaccination destroyed the strains with a thin capsule, and left the strains with a thicker capsule. More: [1], [2], [3].

Serotype A (Hia) incidence in Ontario is already 76% higher than Hib incidence was in the pre-vaccination era.

A few more articles on replacement of serotype B strains with others: [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11].

After the introduction of vaccination, H. influenzae incidence in Israel decreased by 90% by 1996, and remained low in the subsequent years.

Hib vaccination does not always work. Several studies on cases of infection despite vaccination: 423 cases, 40 cases, 251 case, 323 cases, 115 cases, 93 cases, 90 cases, 21 case, 12 cases. More: [1], [2], [3].

The number of H. influenzae cases in the USA between 1991 and 2017:
The conjugated vaccine was introduced in 1988, but until 1991 records of H. influenzae cases were not kept. The CDC claims that before the introduction of the vaccine, 20,000 Hib cases were reported each year, but this data cannot be verified.

When Hib vaccine is given together with the inactivated polio vaccine (IPV), significantly fewer Hib antibodies get produced than would be produced if it were given with a live polio vaccine. It was also found that children that are given Hib and DTaP vaccines at the same time develop significantly fewer tetanus antibodies.
Injection sites were different for the vaccines (one in the arm, and other in the leg). It was previously unknown that giving two vaccines at the same time causes immune interference between them. The biological mechanism of this phenomenon is unknown.

DTaP/Hib combined vaccine produces significantly fewer Hib and tetanus antibodies than would be produced if they were given separately. More: [1], [2], [3].
Nevertheless, in almost all countries, Hib is part of a penta- or hexavalent vaccine, together with IPV and tetanus (Pentacel, Infanrix, etc.)

- DTaP/Hib combined vaccine (with acellular pertussis vaccine) produces 10 times less Hib antibodies than DTP/Hib combined vaccine.
- If the injection site for Hib and DTaP vaccines is the same then 5-15 times less Hib antibodies developed, as compared to choosing different injection sites for the two vaccines.
- DTaP produces significantly fewer diphtheria antibodies than DTP.

After England switched to the acellular pertussis vaccine (DTaP/Hib), an almost 7-times increase in Hib incidence was reported.

There were no increases in Hib incidence after the switch to acellular pertussis vaccine in Sweden and Finland. The authors believe that it is due to the fact that longer breastfeeding periods are common in these countries.

Analysis of data from a Hib vaccine clinical trial in Finland (116,000 children). Hib vaccine increases the risk of juvenile diabetes by 26%. Diabetes occurred 38 months after vaccination.
The vaccine was also tested on mice prone to diabetes. Vaccinated mice developed diabetes significantly more often.
Other studies found a similar increased risk of diabetes, but since these studies were small, the results were statistically insignificant.

Just this side effect alone (increased risk of juvenile diabetes) exceeds the benefit of the vaccine, which should prevent 7 death cases and 7-26 disability cases in 100,000 of those vaccinated. For every child saved from Hib, there will be four people with diabetes.
After the introduction of Hib vaccination in the USA and England the diabetes incidence increased dramatically, especially among children under 4 years of age.
The authors conclude that the potential harm from the vaccine outweighs the potential benefit.

Vaccine studies are based on the theory that the benefits of vaccination significantly exceed the risk of long-term side effects, and therefore long-term safety studies are not necessary.
We found that just the increased risk of one of the side effects (diabetes) already exceeds the decreased risk of meningitis. We believe that the public should be informed that vaccines could cause long-term complications. It will cause the public to demand more adequate safety studies before introducing vaccines, which in turn will lead to development of safer vaccines.

Hib vaccine increases the risk of development to GAD antibodies by 5.9 times, and the risk of IA-2 antibodies development by 3.4 times, which are considered to be autoimmune markers for the development of type-1 diabetes.

According to VAERS, 1,094 people died after receiving the vaccine from 1991 to 2010, and 1,147 people became disabled (that is, 1-2% of all cases). 160 people died of the disease itself during the same period of time.

In this study the authors analyze VAERS. They find 5,179 cases of serious complications and 896 death cases after Hib vaccination, and conclude that the vaccine is safe. More: [1].

Hib vaccine causes Guillain-Barre syndrome sometimes.

DPT/Hib vaccine often leads to cardiorespiratory complications in premature infants, especially if the vaccine is given before the age of 70 days. Adverse events were reported in 38% of infants.

DPT and Hib vaccines increased the risk of apnea (respiratory arrest) and bradycardia (decreased heart rate). More: [1].

The risk of Hib during the first week after vaccination increases by 6 times. According to the CDC, the risk of Hib after vaccination increases by 1.8 times.

This happens because the number of antibodies decreases 2-3 days after vaccination, and than increases on day 7 post-vaccination. That is, in case of asymptomatic Hib infection, vaccination can cause an invasive infection. [1], [2].

Wright introduced the term “negative phase” in 1901 to describe the decrease in bactericidal activity, which he observed during 21 days after typhoid vaccination. This phenomenon was also observed in clinical trials of conjugated and non-conjugated Hib vaccines – for those who already had Hib antibodies, the concentration of antibodies decreased after vaccination. This phenomenon is believed to occur with all four of the existing vaccines. Some believe that the decrease of the number of antibodies happens because the existing antibodies get attached to vaccine antigens. If this happens during asymptomatic colonization, than the risk of invasive disease increases.