Monthly Archives: January 2016

HiB Vaccine (Meningitis)

This is a continuation of a weekly series I’ve been helping to write for an education forum. This is the long version. For the short version, click here.

H. influenzae type B, (c) NHS

H. influenzae type B, (c) NHS

What are the “meningitis vaccines”?

There are two basic types of meningitis: viral and bacterial. There are no vaccines targeting viral meningitis. There are three vaccines targeting causes of bacterial meningitis: HiB, pneumococcal, and meningococcal. Meningococcal was Weekly Topic 03, HiB will be discussed here, and pneumococcal will be discussed in a future Weekly Topic.

According to the CDC Vaccination Schedule (2015), HiB vaccination occurs at 2 mo, 4 mo, 6 mo, and 12/15 mo. No further doses are recommended after the 15 mo dose, even if it was the only dose ever received. It is not recommended after age 5 years in healthy children. It is only available as a combination vaccine, not alone [1, 2]. In Canada, depending on province/territory, a HiB combination vaccine is typically recommended at 2 mo, 4 mo, 6 mo, and 18 mo [3].

 

What is HiB?

Haemohpilus influenzae type B is a bacterium that normally lives in the respiratory tracts of healthy people without causing disease. Up to 5% of the population is infected at a given time, and most children become infected by H. influenzae bacteria by the age of 5, whereby they develop immunity. Infection is more common in crowded housing and settings such as daycare; in fact, in daycare, the infection rate is approximately 15%, 3-15 times the proportion of the general population. Asymptomatic carriers remain infected and contagious for months at a time and the bacteria may easily pass from one person with disease through a long line of asymptomatic carriers before causing disease in another. It is present in the nose and throat and thus is passed by coughing or contact with mucus. However, cribs and toys of daycare children known to be asymptomatic carriers test negative for the bacteria, so contact with contagious children’s belongings is not believed to be a route of transmission. [4]

Because H. influenzae bacteria are a normal part of our respiratory tracts, probably 100% of the population becomes infected at some point, and most infections are asymptomatic, HiB disease is relatively very rare. However, when it does occur, HiB disease may result in sepsis, meningitis, and even death. Among those with HiB disease, approximately 3-6% die and 15-35% suffer permanent neurological sequelae (the most common being partial hearing loss). The most common symptoms of HiB disease include fever, decreased mental status, and stiff neck. [4, 5, 6]

 

How can I prevent or treat HiB in my child?

Conditions that make an individual more susceptible to HiB disease include recent viral infection, smoking or other respiratory irritants, immune suppression (e.g., sickle-cell anemia, absence of a spleen, antibody deficiency disorders, cancer, chemotherapy, etc.), and crowded housing or environment. [4] Avoid exposing your child to these triggers as much as possible by smoking cessation, avoiding crowded living spaces if possible, boosting the immune system, etc., and engaging in a generally healthy lifestyle. If your child has a known exposure to HiB, prompt evaluation by a physician for prophylactic antibiotics may be prudent.

Breastfeeding offers significant protection against HiB, lasting years after weaning [4, 7]. If breastfeeding is not possible due to adoption or other issues, look into relactation, pumping, or donor milk.

Note as discussed later in this post that there is an increased risk of HiB disease in the first week following vaccination. Therefore, if you choose to vaccinate and your child develops symptoms of HiB following vaccination, take it seriously.

 

How effective are the vaccines at preventing asymptomatic carriage?

Several studies have found HiB carriage to be reduced (but not eliminated) by vaccination. [4] Other studies have shown that when HiB vaccination was introduced to a population, HiB disease rates in both vaccinated and unvaccinated infants decreased, but were not eliminated in spite of very high vaccination rates [4]. Because it does not eliminate asymptomatic carriage, and the bacteria can jump from asymptomatic carrier to asymptomatic carrier regardless of the carrier’s vaccine status before causing disease in a susceptible individual, the vaccine cannot be relied upon for herd immunity, as evidenced by continued HiB disease in highly vaccinated populations.

 

How effective is the HiB vaccine?

Prior to the introduction of the vaccine, HiB caused over 80% of all invasive H. influenzae disease among children [8]. The incidence of HiB began to drop before the introduction of the vaccine [9, 10] and continued to drop after vaccination.

The HiB vaccine is of questionable efficacy, with some studies finding it not to be protective in children younger than 18 months, others finding variable efficacy in children over the age of 2, and others finding an increased risk of meningitis immediately following vaccination, with efficacy ranging from 88% to -69%. [6, 11] Newer conjugate vaccines have widely ranging efficacy depending on the population in which it they are tested. For example, the diphtheria-HiB (PRP-D) vaccine ranged from 35% efficacy (in producing an antibody response) in Alaskan Natives and <40% in Finnish children to 87% in another group of Finnish children [12]. Even across a single country, the same vaccine may be associated with vastly varying efficacy, as in one study that found a HiB vaccine that was effective in other areas of the U.S. was not associated with increased antibody response or decreased disease rate in Minnesota [13]. Another study found that HiB-vaccinated children with HiB disease had significantly lower HiB antibody levels than unvaccinated children with HiB disease. This was in spite of appropriate antibody response to other vaccines they had received. It’s thought to be partly due to a genetic defect that affects their ability to produce antibodies specifically to HiB [14].

All of the above estimates of efficacy depend on assumptions regarding what antibody level will be effective at preventing HiB disease, though the CDC states, “the precise level of antibody required for protection against invasive disease is not clearly established.” [15] However, the change in HiB incidence following vaccination can give us an idea of the vaccine’s efficacy.

The introduction of the HiB vaccine was followed by a shift in the dominant strains of H. influenzae from type B (HiB) to predominately nontypeable and type F (HiF)—that is to say, the incidence of infections and invasive disease caused by type B dropped while the incidence of infections and invasive disease caused by other strains increased. The overall incidence of H. influenzae invasive disease and death increased after the introduction of the vaccine. In other words, the introduction of the vaccine was followed by a net increase in H. influenzae-related morbidity and mortality in spite of the decrease in type B disease and death. [8]

This suggests that the HiB vaccine increases the overall risk of H. influenzae morbidity and mortality by increasing one’s risk particularly to non-B H. influenzae. This goes back to the theory of original antigenic sin. In short, people who are vaccinated against one strain are able to produce antibodies only to the antigens included in the vaccine, which handicaps them in fighting other viruses or bacteria that are similar enough to trigger their body’s antibody response but different enough that they don’t have antibodies against the primary antigens. In the case of pertussis, we see how vaccination against PRN-positive B. pertussis increases the risk of PRN-negative B. pertussis, B. parapertussis, and sometimes B. holmesii [16]. In the case of N. meningitidis, we see how the meningococcal vaccine increases the risk of infection with serogroups not included in the vaccine [17]. And here we see that the HiB vaccine increases the risk of H. influenzae strains not included in the vaccine, as discussed above.

The majority of H. influenzae invasive disease occurs in those aged 65 years or older. Furthermore, the introduction of the vaccine in children was followed by a rise in H. influenzae invasive disease and death in adults, especially the vulnerable elderly, demonstrating a negative herd effect. The introduction of the vaccine in children was followed by a net increase in H. influenzae-related morbidity and mortality in those too old to be vaccinated and in the vulnerable. In other words, the vaccine seems to have the opposite effect on the herd—a harmful rather than a helpful effect. [8]

 

Are there other infectious diseases related to HiB vaccination?

The use of other bacterial vaccines, particularly pertussis, seems to have contributed to the sudden increase in HiB infections in the 1970s and 1980s. [18] This led to the creation of the HiB vaccine. However, the introduction of the HiB vaccine also seems to have caused the sudden increase in pneumococcal infections, which are more dangerous and less treatable than HiB. This led to the introduction of the pneumococcal vaccine. However, the introduction of the pneumococcal vaccine seems to have caused the sudden increase in meningococcal infections, which are more dangerous and less treatable than pneumococcal infections. This led to the introduction of the meningococcal vaccine. There is concern that meningococcal vaccination will also be followed by the sudden increase of another more dangerous and less treatable bacterial disease. [5, 19]

 

What are the risks of the vaccine?

Type 1 Diabetes. The HiB vaccine is associated with a 25% increased incidence of type 1 diabetes as compared to vaccinated children who did not receive the HiB vaccine [5, 20, 21, 22; 23, p. 872; 24]. The risk increases with just one dose of HiB vaccine, but is highest in children who received all four doses [25]. In fact, the long-term complications from HiB-vaccine-induced type 1 diabetes alone outweigh the long-term complications from HiB disease if no children were vaccinated against HiB [26].

H. influenzae non-B Invasive Disease. As discussed above, the vaccine is associated with an overall increased incidence in H. influenzae infections and deaths. This is because the increase in non-B infections is more than the decrease in type B infections. The increase in non-B H. influenzae disease and death alone outweighs the drop in type B disease and death.

HiB Invasive Disease. Many studies have found an increased incidence of HiB invasive disease in the first week following vaccination with some types of HiB vaccine. “The evidence favors acceptance of a causal relation between unconjugated PRP vaccine and early-onset Hib disease.” [11] It’s said that this risk is only present with unconjugated vaccines (which we no longer use in the U.S.) [11], but it’s actually more common with conjugated vaccines (which we currently use in the U.S.) [27]. At times, this has occurred as early as 3 hours after HiB vaccination [28] and after a second HiB vaccine when there was no reaction to the first [29]. It’s important to note that this is not due to injection with live bacteria—that is, the contents of the vaccine do not directly cause the infection. Rather, it may be due to two related issues. One is that a dramatic decrease in antibody levels occurs in the first few days after vaccination due to the antibodies already present in the child pre-vaccination being quickly used up in fighting the antigens found in the vaccine, leaving the child susceptible to HiB in the environment due to inadequate antibody levels [28]. Another is the vaccine causing a briefly suppressed immune system, which makes the recipient more susceptible to disease. This is called “provocation disease” and was first recorded in medical literature in the 1960s in relation to polio, tuberculosis, and a few other diseases occurring secondary to vaccination [30, pp. 179-188].

Transverse Myelitis. There may be an association between the vaccine and transverse myelitis. This association is based on VAERS reports, not on medical literature. “The evidence is inadequate to accept or reject a causal relation between Hib vaccines and transverse myelitis.” [11]

Guillain-Barré Syndrome (GBS). There may be an association between the vaccine and transverse myelitis. This association is based on a published case series and VAERS reports. “The evidence is inadequate to accept or reject a causal relation between Hib vaccines and GBS.” [11]

Thrombocytopenia. This possible association is based on data from a HiB vaccine trial conducted in adults, as well as VAERS reports. “The evidence is inadequate to accept or reject a causal relation between Hib vaccines and thrombocytopenia.” [11]

SIDS. There are VAERS reports of SIDS cases occurring in close temporal association to HiB vaccination. [31] The association does not seem to have been studied in depth.

Asthma and Allergies. A Swiss study found HiB-vaccinated children to have a higher incidence of asthma and allergies as compared to HiB-unvaccinated children [32]. Studies in guinea pigs found asthmatic reactions to begin as early as four days following HiB vaccination [33].

Epiglottitis. The same Swiss study referenced above [32] found that an increase in epiglottitis was associated with the HiB-vaccine-associated increase in asthma and allergies.

Autism. The autism rate did not change significantly after the introduction of the MMR and DTP vaccines. However, it began to rise significantly after the introduction of the HiB and Hep B vaccines. Many parents have noted autistic regression following the MMR, which used to be given at the same time as the HiB vaccine. [34] Correlation does not equal causation, but a study comparing the autism rates in children who did and children who did not receive the HiB vaccine would be interesting. To my knowledge, such a study has not been conducted.

Encephalitis. There is at least one report of encephalitis occurring after HiB vaccination, but the child was simultaneously vaccinated against DPT (known to be associated with encephalitis) and OPV, so it’s uncertain whether the HiB vaccine can be blamed in this case. [35]

Others. Convulsions (seizures) and allergic reactions to the vaccine (including anaphylaxis) have also been reported. [36]

 

What vaccines are offered against HiB?

In the U.S. and Canada, there are no HiB-only vaccines. All HiB vaccines are combo shots. (NOTE: These ingredients lists are not complete; they only list the most alarming ingredients.)

  • ActHIB: tetanus-HiB (tetanus and HiB antigens, ammonium sulfate, formaldehyde, casein [milk protein]) [37]
  • Pentacel: DTaP-IPV-HiB (contains ActHIB; diphtheria, tetanus, acellular pertussis, 3 strains of inactivated poliovirus, and HiB antigens, aluminum, polysorbate 80, formaldehyde, cow serum, 2-phenoxyethanol, neomycin, polymyxin B, ammonium sulfate, casein [milk protein], and MRC-5 [aborted fetus cells]) [38]
  • MenHibrix: Men C/Y-tetanus-HiB (meningococcal C/Y, HiB, and tetanus antigens, formaldehyde) [39]
  • PedvaxHiB: Men B-HiB (meningococcal B and HiB antigens, aluminum) [40]
  • Hiberix: tetanus-HiB (tetanus toxoid and HiB antigens, formaldehyde, lactose) [41]
  • Comvax: Hep B-Men B-HiB (contains PedvaxHiB; hepatitis B, meningococcal B, and HiB antigens, yeast cells, soy, aluminum, and formaldehyde) [42]

 

So what’s the bottom line?

The bottom line is that HiB is so common that 100% of the population carries it at some point and virtually 100% of the population is immune to it by age 5. The vaccine does not prevent asymptomatic carriage and so cannot be relied upon for herd immunity. The vaccine simultaneously decreases the risk of H. influenzae type B, which makes up a minority of strains today, and increases the risk of all other H. influenzae strains. Vaccination of children is associated with an overall increased risk of H. influenzae invasive disease and death in both children and adults, especially the elderly. HiB vaccination is also associated with increased incidence of other more dangerous and less treatable bacterial infections. The vaccine is associated with type 1 diabetes, and the complications of vaccine-induced type 1 diabetes when vaccinated alone outweighs the risk of HiB disease when not vaccinated. The vaccine is also associated with other adverse events such as asthma, allergies, epiglottitis, an increased incidence of HiB disease in the first week after vaccination, and more. The bottom line is the risk of death is higher with the vaccine than without.

 

References

[1] http://www.cdc.gov/vaccines/schedules/downloads/child/0-18yrs-child-combined-schedule.pdf

[2] http://www.cdc.gov/vaccines/vpd-vac/hib/vac-faqs-hcp.htm

[3] http://healthycanadians.gc.ca/healthy-living-vie-saine/immunization-immunisation/children-enfants/schedule-calendrier-table-1-eng.php

[4] Evans, A.S. & Brachman, P.S. (2013). Bacterial Infections of Humans: Epidemiology and Control (Fifth Ed.). (pp. 315-316) New York: Springer-Verlag New York Inc.

[5] https://www.youtube.com/watch?v=QVE2l2RJ8lY

[6] http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/hib.pdf

[7] http://www.ncbi.nlm.nih.gov/pubmed/10569222

[8] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3322072/

[9] http://www.ncbi.nlm.nih.gov/pubmed/8417239

[10] http://www.unboundmedicine.com/medline/citation/8143010/Eradication_of_Haemophilus_influenzae_type_b_disease_in_southern_California__Kaiser_UCLA_Vaccine_Study_Group_

[11] http://www.ncbi.nlm.nih.gov/books/NBK236299/

[12] http://www.cdc.gov/mmwr/preview/mmwrhtml/00041736.htm

[13] http://www.ncbi.nlm.nih.gov/pubmed/2785147

[14] http://www.ncbi.nlm.nih.gov/pubmed/3491315

[15] http://www.cdc.gov/mmwr/preview/mmwrhtml/00023705.htm

[16] https://schaabling.wordpress.com/2015/12/18/pertussis-whooping-cough/

[17] Weekly Topic 03: Meningococcal Vaccine (Meningitis)

[18] “Several factors indicate that mass immunisation with pertussis and other non-Hib vaccines may have been responsible for the unprecedented epidemics of invasive bacterial infections such as Hib, during the 1970’s and 1980’s.” (p. 315) Miller, N.Z. (2008). Vaccine Safety Manual.

[19] http://www.wellwithin1.com/HibPneuButler1993to2006letters.pdf

[20] http://www.ncbi.nlm.nih.gov/pubmed/14679101

[21] http://www.ncbi.nlm.nih.gov/pubmed/12482192

[22] http://www.ncbi.nlm.nih.gov/pubmed/12793601

[23] http://care.diabetesjournals.org/content/23/6/872.long

[24] Shoenfeld, Y., Agmon-Levin, N., & Tomljenovic, L. (2015). Vaccines and Autoimmunity (pp. 185-190). Hoboke, NJ: Wiley Blackwell.

[25] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1116914/

[26] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1114674/

[27] http://www.ncbi.nlm.nih.gov/pubmed/1669664

[28] http://www.ncbi.nlm.nih.gov/pubmed/8762955

[29] http://www.ncbi.nlm.nih.gov/pubmed/9133234

[30] http://soilandhealth.org/wp-content/uploads/02/0201hyglibcat/020152.vac.haz/vac.haz.pdf

[31] http://www.ncbi.nlm.nih.gov/books/NBK236284/

[32] http://www.ncbi.nlm.nih.gov/pubmed/9027536

[33] http://www.ncbi.nlm.nih.gov/pubmed/6335351

[34] https://web.archive.org/web/20041029232155/http://mothering.com/articles/growing_child/vaccines/biochemistry.html

[35] http://www.ncbi.nlm.nih.gov/pubmed/8103131

[36] http://www.ncbi.nlm.nih.gov/pubmed/3497381

[37] http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM109841.pdf

[38] http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM109810.pdf

[39] http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM308577.pdf

[40] http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM253652.pdf

[41] http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM179530.pdf

[42] http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM109869.pdf

HiB Vaccine (Meningitis) SHORT

This is the short version. For the long version with references, click here.

H. influenzae type B, (c) NHS

H. influenzae type B, (c) NHS

What are the “meningitis vaccines”?

There are two basic types of meningitis: viral and bacterial. There are no vaccines targeting viral meningitis. There are three vaccines targeting causes of bacterial meningitis: HiB, pneumococcal, and meningococcal. Meningococcal was Weekly Topic 03, HiB will be discussed here, and pneumococcal will be discussed in a future Weekly Topic.

The HiB vaccine is generally given at 2, 4, 6, and 12-18 months (though it varies by country and province).

 

What is HiB?

Haemohpilus influenzae type B (HiB) is a bacterium that normally lives in the respiratory tracts of healthy people without causing disease. Up to 5% of the population is infected at a given time, and most children become infected by H. influenzae bacteria by the age of 5, whereby they become immune. Infection is more common in crowded housing and settings such as daycare; in fact, in daycare, the infection rate is approximately 15%. Asymptomatic carriers remain infected and contagious for months at a time and the bacteria easily pass through a long line of asymptomatic carriers before causing disease in someone. It is present in the nose and throat and thus is passed by coughing or contact with mucus.

Because (a) H. influenzae bacteria are a normal part of our respiratory tracts, (b) 100% of the population becomes infected at some point, and (c) most infections are asymptomatic, HiB disease is relatively very rare. However, when it does occur, HiB disease may result in sepsis, meningitis, and even death. Among those with HiB disease, approximately 3-6% die and 15-35% suffer permanent neurological sequelae (the most common being partial hearing loss). The most common symptoms of HiB disease include fever, decreased mental status, and stiff neck.

 

How can I prevent or treat HiB in my child?

Conditions that make an individual more susceptible to HiB disease include recent viral infection, smoking or other respiratory irritants, immune suppression, and crowded housing or crowded environment. Avoid exposing your child to these triggers as much as possible by smoking cessation, avoiding crowded living spaces if possible, boosting the immune system, etc., and engaging in a generally healthy lifestyle. If your child has a known exposure to HiB, prompt evaluation by a physician for prophylactic antibiotics may be prudent.

Breastfeeding offers significant protection against HiB, lasting several years after weaning. If breastfeeding is not possible due to adoption or other issues, look into relactation, pumping, or donor milk.

 

How effective are the vaccines at preventing asymptomatic carriage?

HiB carriage is reduced but not eliminated by vaccination. Extremely high vaccination rates reduce but do not eliminate HiB disease. As mentioned above, the bacteria can jump from asymptomatic carrier to asymptomatic carrier regardless of the carrier’s vaccine status before causing disease in a susceptible individual. Therefore, because the vaccine does not prevent asymptomatic carriage, it cannot be relied upon for herd immunity.

 

How effective is the HiB vaccine?

Prior to the introduction of the vaccine, HiB caused over 80% of all invasive H. influenzae disease among children. The incidence of HiB began to drop before the introduction of the vaccine and continued to drop after the introduction of the vaccine.

The HiB vaccine’s efficacy ranges from -69% (increased risk) to 88% (decreased risk), with the efficacy seeming to depend not only on the type of HiB vaccine used, but also on the populations in which it was used. It varies drastically even from state to state or province to province in the same country.

HiB vaccination is associated with *decreased* type B H. influenzae (HiB) disease and death but *increased* non-B H. influenzae disease and death. The overall net effect of HiB vaccination has been **a net increase in H. influenzae disease and death**. This is likely due to the crippling effect of “original antigenic sin,” where the body is trained to produce antibodies against one strain and becomes unable to produce antibodies against different strains. This makes the vaccinated person at **increased risk of contracting other strains**. Furthermore, the greatest increase in H. influenzae disease and death was in the (unvaccinated) elderly. If herd immunity existed with this vaccine, we would expect a decreased risk in the unvaccinated. However, HiB vaccination of infants was followed by an increased risk in all age groups (vaccinated or unvaccinated) but especially in the (unvaccinated) elderly, suggesting a negative herd effect.

 

Are there other infectious diseases related to HiB vaccination?

It appears that pertussis vaccination caused an increase in (more dangerous, less treatable) HiB, hence the HiB vaccine; HiB vaccination caused an increase in pneumococcal (even more dangerous, less treatable) infections, hence the PCV vaccine; and the PCV caused an increased in (still more dangerous, less treatable) meningococcal infections, hence the MCV vaccine. There is concern that the MCV will also be followed by the sudden increase of another more dangerous and less treatable bacterial disease.

 

What are the risks of the vaccine?

Type 1 Diabetes. The HiB vaccine increases the risk of type 1 diabetes with just one dose, and the risk increases with more doses. In fact, the long-term complications from HiB-vaccine-induced type 1 diabetes alone outweigh the long-term complications from HiB disease if no children were vaccinated against HiB.

H. influenzae non-B Invasive Disease. As discussed above, the vaccine is associated with an overall increased incidence in H. influenzae infections and deaths. This is because the increase in non-B infections is more than the decrease in type B infections. The increase in non-B H. influenzae disease and death alone outweighs the drop in type B disease and death.

HiB Invasive Disease. HiB vaccination increases the risk of HiB invasive disease and death in the first week after vaccinating. This has happened as shortly as 3 hours after vaccinating and after a second vaccine when there was no reaction to the first.

Others. Other known or suspected reactions include transverse myelitis, Guillain-Barre Syndrome, thrombocytopenia, SIDS, asthma and allergies, epiglottitis, autism, encephalitis, convulsions (seizures), and allergic reactions to the vaccine (including anaphylaxis).

 

So what’s the bottom line?

The bottom line is that HiB is so common that 100% of the population carries it at some point and virtually 100% of the population is immune to it by age 5. The vaccine does not prevent asymptomatic carriage and so cannot be relied upon for herd immunity. The vaccine simultaneously decreases the risk of H. influenzae type B, which makes up a minority of strains today, and increases the risk of all other H. influenzae strains. Vaccination of children is associated with an overall increased risk of H. influenzae invasive disease and death in both children and adults, especially the elderly. HiB vaccination is also associated with increased incidence of other more dangerous and less treatable bacterial infections. The vaccine is associated with type 1 diabetes, and the complications of vaccine-induced type 1 diabetes alone outweighs the risk of HiB disease when not vaccinated. The vaccine is also associated with other adverse events such as asthma, allergies, epiglottitis, an increased incidence of HiB disease in the first week after vaccination, and more. The bottom line is the risk of death is higher with the vaccine than without.

 

Meningococcal Vaccine (Meningitis) (SHORT)

This is the short version of the meningococcal vaccine post. For the long version and references, check here.

400px-NMeningitidis

What are the “meningitis vaccines”?

There are two basic types of meningitis: viral and bacterial. There are no vaccines targeting viral meningitis. There are three vaccines targeting causes of bacterial meningitis: HiB, pneumococcal, and meningococcal. Meningococcal will be discussed here and the others in future Weekly Topics.

What is meningococcus?

Neisseria meningitidis, the meningococcal bacteria, is passed by coughing or contact with saliva and is normally present in the respiratory tracts of healthy people without causing disease. Probably 100% of people become infected at some point and about 5-35% of the population is infected with the bacteria at any time. Asymptomatic carriers carry the bacteria for months or even years.

N. meningitidis is divided into serogroups (not strains). Serogroup B is responsible for 60% of U.S. cases of meningococcal disease and is targeted by one vaccine. Serogroups A, C, Y, and W-135 are less common and are targeted by another vaccine (some countries have a C-only vaccine). Natural infection with one serogroup or with a different species called N. lactamica confers immunity to all serogroups and it’s rare for an unvaccinated individual to become infected with one serogroup and later become infected with a different serogroup.

According to the CDC, “For unknown reasons, incidence has declined since the peak of disease in the late 1990s…. This decline began before implementation of routine use of meningococcal vaccines in adolescents and have occurred in all serogroups.” Last year (2014), there were a total of 386 meningococcal disease cases and an estimated 39-58 deaths.

Meningococcal disease occurs most frequently in those with suppressed immune systems. Risk factors and prevention techniques are in the longer version of this post.

How effective are the vaccines at preventing asymptomatic carriage?

One study suggested that A/C/Y/W-135 vaccination may reduce the length of (but not eliminate) asymptomatic carriage. However, the vaccine against serogroup B does not prevent asymptomatic carriage. Thus, the vaccines should not be relied upon for herd immunity.

How effective are the vaccines at preventing disease?

As discussed above, natural infection with one serogroup or a related species confers immunity against all serogroups. However, the vaccine potentially protects against only the serogroup in the vaccine. It’s said to be 85% effective, but has never been proven to prevent disease, only to induce an antibody response.

As also discussed above, it’s rare for an unvaccinated individual to become infected with one serogroup and later become infected with another serogroup. However, when N. meningitidis infects a vaccinated individual, the bacteria can change its serogroup in a matter of days to one against which the vaccine offered no protection, whereby it causes disease in and kills the vaccinated individual.

How great is the antibody response produced by the vaccine?

As discussed above, the vaccine has never been proven to prevent disease, only to induce an antibody response. However, following three doses, about half of recipients do not develop an appropriate antibody response, and following four doses, 87% do not respond. Furthermore, the antibodies wane in less than 7 months.

In fact, New Zealand saw an increased incidence of meningococcal disease following three doses of the vaccine. After the four-year vaccination campaign, the New Zealand Herald reported on 109 cases of the vaccine-targeted strain in vaccinated people. For 2006-2008, there were 12 meningococcal deaths, all in vaccinated children. There were no meningococcal deaths in unvaccinated children. Furthermore, the meningococcal disease rate was dropping prior to the introduction of the vaccine but increased during the vaccination campaign.

Is the vaccine safe?

The short version is a resounding no. We will assume the previously discussed false statistic of 85% efficacy is true and combine that with the package inserts’ serious adverse event rate of 1% (A/C/Y/W-135) and 2% (B), the CDC’s estimated 0.3% rate of death following adverse events, and Fall 2015’s U.S. college enrollment of 20.2 million students. If all U.S. college students receive only one injection of each meningococcal vaccine in one year, there will be an estimated 606,000 serious adverse events and 1,818 deaths from meningococcal vaccination of all U.S. college students. Compare that to last year’s 386 meningococcal disease cases and estimated 39-58 deaths in all age groups in the U.S.

Are the meningococcal vaccines linked to autoimmune diseases?

Meningococcal serogroup C or A/C/Y/W-135 vaccines have been definitively or tentatively linked to three autoimmune diseases: Henoch-Schönlein purpura, bullous phemigoid, and Guillain-Barré Syndrome. The serogroup B vaccine took so long to develop primarily because its antigens look very similar to structures on human brain cells, which may increase the risk of neurological autoimmune diseases. However, the serogroup B vaccine is too new to know yet whether it increases the risk of autoimmune diseases.

So what’s the bottom line?

The bottom line is that meningococcal bacteria infect probably 100% of the population and exceptionally rarely cause disease. Natural infection with one serogroup confers immunity against all serogroups whereas vaccination provides immunity only against the serogroups targeted by the vaccine and increase one’s risk to serogroups not included in the vaccine. After infecting a vaccinated person, the bacteria can change their serogroup to one against which the vaccinated individual has no protection. Furthermore, in some populations, vaccination was demonstrated to increase the incidence of meningococcal disease and death. The risk of death from the vaccine far outweighs the risk of death from the disease. The vaccine does not prevent asymptomatic carriage, so the vaccine offers no herd immunity effect.

Meningococcal Vaccine (Meningitis)

In another forum, I shared the following. I’m publishing it here to have a shareable source. For the short and sweet version, check here.

Weekly Topic 03: Meningococcal Vaccine (Meningitis)

400px-NMeningitidis

 

What are the “meningitis vaccines”?

There are two basic types of meningitis: viral and bacterial. There are no vaccines targeting viral meningitis. There are three vaccines targeting causes of bacterial meningitis: HiB, pneumococcal, and meningococcal. Meningococcal will be discussed here and the others in future Weekly Topics. According to the CDC Vaccination Schedule (2015), the meningococcal vaccine is given at 11-12 years and again at 16-18 years [1]. In Canada, depending on province/territory, meningococcal vaccines may be given in infancy, in grade school, and/or in high school [2].

 

What is meningococcus?

Neisseria meningitidis, the meningococcal bacteria, is passed by coughing or contact with saliva and is normally present in the respiratory tracts of healthy people without causing disease [3, 4, 5]. In fact, probably no one escapes infection. Symptomatic disease is quite rare for N. meningitidis. As such, 100% of the population, vaccinated or not, are asymptomatic carriers at some point in their lives. In fact, at any time, 5-35% of the population is silently carrying the bacteria, though the numbers often rise to nearly 100% in close quarters, such as military barracks and college campuses [4]. (However, despite the widespread rate of infection on college campuses, the CDC states, “Overall incidence [of meningococcal disease] among college students usually is similar to or somewhat lower than that observed among persons in the general population of similar age.” [6] On the other hand, the rate among college students is 3.2/100,000 for those living in dormitories versus 1.0/100,000 for those living off-campus [6].) Asymptomatic carriers carry the bacteria for many months at a time, sometimes for years, and are contagious [4, 5].

There are two basic types of N. meningitidis, capsular bacteria (which have serogroups and are considered pathogenic, meaning they can cause disease) and noncapsular bacteria (which do not have serogroups and are considered nonpathogenic, meaning they cannot cause disease). About one third of carriers are infected with a type that is considered nonpathogenic [4]. The most common serogroups today are B (targeted by one vaccine) and A, C, Y, and W-135 (targeted by another vaccine). Serogroup B is now responsible for 60% of U.S. cases of meningococcal disease [7]. Natural infection with one serogroup confers immunity against all serogroups [4, 5]. Though it’s not fully understood why at this time, natural infection with another similar nonpathogenic species, N. lactamica, also confers immunity to all serogroups of N. meningitidis [8, 9]. It’s quite rare for an unvaccinated individual to be infected with one serogroup and then later become infected with a different serogroup [4].

According to the CDC (2013), “For unknown reasons, incidence has declined since the peak of disease in the late 1990s, and approximately 800–1,200 cases are reported annually in the United States. This decline began before implementation of routine use of meningococcal vaccines in adolescents and have occurred in all serogroups.” [10] However, their estimated number of cases is not supported by their own more recent data, which found 386 (2014), 556 (2013), 551 (2012), 759 (2011), and 980 (2010) cases for a 5-year average of 646 cases per year [11]. In the U.S. last year (2014), there were a total of 386 meningococcal disease cases and estimated 39-58 deaths (given the CDC’s estimated case fatality rate of 10-15%) [10, 11].

Meningococcal disease occurs more frequently in the winter and studies have found that the sickest children with meningococcal meningitis are those with extremely low vitamin C levels. This gives us a hint as to why some children are completely unaffected by the bacteria, which live harmlessly in their noses and throats, while others are susceptible to meningitis—namely, that their immune systems are better equipped to fight the bacteria. Factors which make a child or adult susceptible to meningococcal meningitis may include: tonsillectomies (tonsils are immune system glands in the throat), antibiotic use, poor diet, low vitamin C, smoking, recent viral infection, immune depression (such as by over-vaccination, use of acetaminophen/paracetamol, antihistamines, and antibiotics), and lack of exercise. [3, 5, 12] Natural techniques for prevention and healing include adequate rest, good nutrition, fresh air, not sharing anything that might be tainted with saliva (e.g., food, drinks, eating utensils, towels, lipstick, etc.), frequent hand-washing, gargling or washing the nasal passages with colloidal silver or with a Lugol’s solution and a netty pot, increased vitamin C intake (3-6 G/day for an adolescent/adult), and increased vitamin D intake. In the case of a known exposure, antibiotics (along with a probiotic) may be prudent [7].

 

How does meningococcus evolve in response to vaccination?

The most common serogroups were once A, C, Y, and W-135, and the first vaccines targeted all four of these serogroups or C alone. However, serogroup B then became the most common serogroup, and so a new vaccine specifically targeting serogroup B was added. Given the microevolutionary history of other vaccine-targeted species, it would not come as a surprise to find a new serogroup not targeted by the vaccine appear in the near future.

Unfortunately, what we find with most vaccines is that the strains not covered by the vaccine are the more dangerous strains, and they become more common when the covered strains are selectively reduced. If there is no vaccine, children are typically infected by the most common strains, which are generally less dangerous and therefore give them immunity against all strains with lower associated risk. [3] (Examples: pneumococcus and HiB, which will be covered in future Weekly Topics.) However, when the more dangerous strain becomes the most common, cases in both vaccinated and unvaccinated are more likely (but in the vaccinated, most likely) to be caused by the dangerous strains not covered by the vaccine.

Dr. Tenpenny also addresses this issue. She explains that the vaccine doesn’t just increase other more dangerous strains that were kept in control by a high quantity of the less dangerous strains, but that some vaccines increase other species by eliminating ones that kept them in control. She explains that was the case with HiB, where the vaccine resulted in an increase in pneumococcal bacteria, hence a pneumococcal vaccine, which resulted in an increase in meningococcal bacteria, hence a meningococcal vaccine. [13] Time will tell what species comes next.

 

How effective are the vaccines at preventing asymptomatic carriage?

One study suggested that vaccination against serogroups A, C, Y, and W-135 may reduce the length of (but not eliminate) asymptomatic carriage [4]. However, the vaccine against serogroup B does not prevent asymptomatic carriage [3, 14]. Thus, the vaccines should not be relied upon for herd immunity.

 

How effective are the vaccines at preventing disease?

As discussed above, natural infection with one serogroup or with a similar species confers immunity against all serogroups; however, vaccination only provides potential protection against the serogroups included in the vaccine [4, 5]. It’s said to be 85% effective against the serogroup(s) included in the vaccine [15]. However, whether the vaccine actually protects against the serogroup(s) in question has not yet been proven. In fact, the first vaccine against serogroup B, Bexsero, was rejected by the U.K. because the efficacy studies demonstrated only that children developed quickly waning antibodies, not that it protected against disease, and, though accepted by the U.K. government, the same issue existed with the serogroup C vaccine [7, 16]. In fact, one country’s post-vaccine review found an increased risk of meningococcal disease following vaccination [17].

How does this happen? The term “original antigenic sin” describes a phenomenon wherein vaccination against one strain or serogroup trains the body to respond only to the antigens in the vaccine strain/serogroup, thereby handicapping the body’s immune response to different but related strains or species, which have some familiar and some unfamiliar antigens [16]. This may be why the vaccine may increase rather than decrease the risk of meningococcal disease [17], as mentioned above, and why there are VAERS reports of college students developing bacterial meningitis within weeks of getting the vaccine [12].

Furthermore, as discussed above, it’s quite rare for an unvaccinated individual to be infected with one serogroup and then later become infected with a different serogroup [4]. However, in the presence of vaccination, N. meningitidis can and does first infect the vaccinated individual and then change its own serogroup within a few days to one against which the vaccine offered no protection and thereby cause disease in and even kill the vaccinated individual [18]. This possibility was highlighted in a case report published in the New England Journal of Medicine, in which they concluded, “The rapidity of the serogroup switching arouses concern about the induction of herd immunity against single serogroups by vaccination programs in which capsular antigens (e.g., serogroup C polysaccharides) are used. Without lowering the incidence of meningococcal disease in the long run, such programs may rapidly increase the incidence of serogroup B meningococcal disease, for which no vaccine is available.” [18] Although a serogroup B vaccine is now available, the same rule would apply to any other or any new serogroups in the future—namely, that the bacteria can and will simply change serogroup after infecting the vaccinated individual to one against which the vaccinated individual has no protection, making vaccination essentially of no effect.

 

So if there’s no proof that the vaccine actually prevents disease, does it at least result in an antibody response?

Many, perhaps a majority, of those vaccinated don’t develop an appropriate antibody response to the vaccine. In one study of infants given four doses of the vaccine at 6 wks, 3 mo, 5 mo, and 10 mo, about half did not develop an appropriate antibody response following the third dose, while 87% did not respond following the fourth dose [19]. In fact, the New Zealand Ministry of Health found that children had an **increased** risk of meningococcal disease following the third dose and responded by adding a fourth dose, ostensibly hoping this would reduce the risk but with no evidence to that effect [17].

Furthermore, the antibodies produced in response to meningococcal vaccination wane very quickly. According to the lead author of the MenZB (New Zealand’s serogroup B vaccine) studies, it resulted in less than 7 months of “protection” as determined by antibody levels [20].

New Zealand utilized fearmongering to introduce meningococcal vaccination, where the “informed consent” for the “MenZB” meningococcal vaccine included a photo of a dying child. [21] However, following the four-year vaccination campaign, the New Zealand Herald reported that there were 109 cases of the vaccine-covered strain of meningococcal bacteria in vaccinated people, with 60 partially and 49 fully vaccinated. The consent failed to mention that the immunity fell below protective levels within months, as discussed above, and “officials were determined to conceal anything that might cause unease.” For 2006, 2007, and 2008, there were 12 meningococcal deaths, and all were in vaccinated children. There were no meningococcal deaths in unvaccinated children. Furthermore, the total meningococcal death rate was steadily declining prior to the introduction of the vaccine, but shot upward during the vaccination campaign. [14, 20] Yet in spite of this, health officials claimed they were scrapping the vaccination campaign because the vaccine had successfully ended the epidemic [22].

 

Is the vaccine safe?

The short version is a resounding no. The group at highest risk of developing meningococcal disease is infants, due to immature immune systems, followed by college students, due to crowded housing [6]. However, the number of expected deaths from meningococcal disease in all age groups per year in the U.S. is significantly outnumbered by the expected number of deaths due to meningococcal vaccination of U.S. college students, assuming an 85% efficacy rate (and, as mentioned above, there’s no evidence to support an alleged 85% efficacy rate).

As mentioned above, there were a total of 386 meningococcal disease cases in all age groups last year (2014) for the entire U.S. and estimated 39-58 deaths (given the CDC’s estimated case fatality rate of 10-15%) [10, 11]. If both a vaccine for A, C, Y, and W-135 and a vaccine for B is administered to every Colorado college student, judging by the package inserts’ estimated serious adverse event rate of 1% (A, C, Y, and W-135) and 2% (B), and the CDC Pink Book’s estimated rate of death secondary to serious adverse events from meningococcal vaccination of 0.3%, we can anticipate 12,000 serious adverse events and 36 deaths due to the vaccines among the approximately 400,000 college students in Colorado alone [11, 15]. In fall of 2015, the anticipated college enrollment for the entire U.S. is 20.2 million students [23]. That correlates to an estimation of 202,000 serious adverse events and 606 deaths from A, C, Y, and W-135 vaccination and 404,000 serious adverse events and 1,212 deaths from B vaccination, for a total of 606,000 serious adverse events and 1,818 deaths from meningococcal vaccination of all U.S. college students as compared to 386 meningococcal cases and an estimated 39-58 deaths of all U.S. residents in all age groups. That’s assuming each student has only one of each vaccine per year, although it properly involves a 2- to 4-dose priming series [10] and, given the short duration (less than 7 months) of presumed “protective” antibody levels after vaccination, as discussed above, should actually involve biannual boosters.

 

So if there’s no evidence of efficacy or safety, why was meningococcal vaccination pushed? And why does the U.S. recommend it for adolescents rather than for the highest risk category, infants?

A meningococcal vaccine targeting A, C, Y, and W-135 serogroups was first introduced in the U.S. in 1981, but wasn’t considered for government coverage until 2004. (The U.S. government buys and distributes over half of all vaccines in the U.S., so government coverage is critical for widespread use of a vaccine.) At that time, it was known not to be cost effective due to the extremely rare incidence of meningococcal meningitis and high cost of the vaccine, to say nothing of its effectiveness or safety. However, teens were rarely vaccinated with the recommended adolescent vaccines, so it was suggested that parents might be more willing to get their teens vaccinated in general if they could be frightened into accepting the meningococcal vaccine: “Frightening parents about the consequences of failing to vaccinate their children will most likely be part of the campaign. For that task, meningococcal meningitis is ideal.” [24]

In New Zealand, it was pushed for manifold corrupt reasons, as uncovered by a pair of investigative journalists [25].

 

Are the meningococcal vaccines linked to autoimmune diseases?

Meningococcal serogroup C or A, C, Y, and W-135 vaccines have been linked to two autoimmune diseases, Henoch-Schönlein purpura and bullous phemigoid, and tentatively linked to a third autoimmune disease, Guillain-Barré Syndrome [26].

The serogroup B antigens are “autoantigens,” meaning they are very similar to structures on human cells. Although natural infection with meningococcal serogroup B does not result in autoimmunity, meaning that the body does not react to the autoantigens on the bacteria but rather reacts only to the bacterium-specific antigens, vaccine adjuvants force the immune system to react to the antigens included in the vaccine. For this reason, the human body may mistake “self” structures for autoantigens included in the vaccine and begin attacking itself. This is the basis of autoimmune diseases and one reason why vaccines cause autoimmune diseases, though it may take anywhere from days to years for the self-inflicted damage to become so severe that symptoms develop. Aware of this issue, serogroup B vaccine theorists and developers have discussed the risk of MenB vaccines causing autoimmune diseases, specifically autoimmune diseases of the central nervous system (brain and spinal cord) because sugar sequences on the surface of the bacterial capsule are very similar to sugar sequences on human brain and nerve cells. For this reason, current MenB vaccines generally use subcapsular antigens (i.e., antigens that appear inside the capsule rather than on its surface). However, MenB vaccines are too new and relatively untested (having been fast-tracked through the FDA approval process and similar approval processes in other countries) for us to know at this time whether it is associated with the development of autoimmune diseases [7, 8, 9, 26].

 

What vaccines are offered against meningococcus?

(NOTE: These ingredients lists are not complete; they only list the most alarming ingredients.)

In the U.S., the A/C/Y/W-135 meningococcal vaccines are

  • Menomune by Sanofi (contains antigens from serogroups A, C, Y, and W-135; casein [a milk protein]; lactose; and 25 mcg thimerosal [27, 28])
  • Menactra by Sanofi (contains antigens from serogroups A, C, Y, and W-135; diphtheria toxoid; casein; 2.66 mcg formaldehyde; and ammonium sulfate [29])
  • Menveo by Novartis (contains antigens from serogroups A, C, Y, and W-135; diphtheria toxoid; 0.3 mcg formaldehyde; amino acids; and yeast [30])

In the U.S., the B serogroup meningococcal vaccines are

  • Bexsero by Novartis (contains antigens from serogroup B; 1.5 mg aluminum hydroxide; histidine; sucrose; 0.01 mcg kanamycin; and E. coli [31])
  • Trumenba by Pfizer (contains antigens from serogroup B; 0.25 mg aluminum phosphate; 0.018 mg polysorbate 80; histidine; and E. coli [32])

 

So what’s the bottom line?

The bottom line is that meningococcal bacteria infect probably 100% of the population and exceptionally rarely cause disease. Natural infection with one serogroup confers immunity against all serogroups whereas vaccination provides immunity only against the serogroups targeted by the vaccine and increase one’s risk to serogroups not included in the vaccine. After infecting a vaccinated person, the bacteria can change their serogroup to one against which the vaccinated individual has no protection. Furthermore, in some populations, vaccination was demonstrated to increase the risk of meningococcal disease and death. The risk of death from the vaccine far outweighs the risk of death from the disease. The vaccine does not prevent asymptomatic carriage, so the vaccine offers no herd immunity effect.

 

Sources:

A NOTE ON SOURCES: There are two sources below (5 and 19) that are paywalled, meaning you have to pay to read them. Free full-text versions were available on www.whale.to, and so those are the links I provided; however, this site is not considered a credible source, so I advise against using it in any debates or essays.

[1] http://www.cdc.gov/vaccines/schedules/downloads/child/0-18yrs-child-combined-schedule.pdf

[2] http://healthycanadians.gc.ca/healthy-living-vie-saine/immunization-immunisation/children-enfants/schedule-calendrier-table-1-eng.php

[3] https://www.facebook.com/groups/gentleinformants/permalink/1004672592923652/

[4] http://femsre.oxfordjournals.org/content/31/1/52.long?view=long&pmid=17233635

[5] http://www.whale.to/vaccines/meningitis5.html

[6] http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5407a1.htm

[7] http://tenpennyimc.com/2013/11/17/meningitis-at-princeton-7-things-you-need-to-know/

[8] http://vaccineresearchlibrary.com/scream-14-meningococcal-vaccines/

[9] http://m.cid.oxfordjournals.org/content/50/Supplement_2/S54.full

[10] http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6202a1.htm

[11] http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6352md.htm

[12] http://vaxtruth.org/2011/10/meningococcal/

[13] https://www.youtube.com/watch?v=QVE2l2RJ8lY

[14] http://www.nzherald.co.nz/meningococcal/news/article.cfm?c_id=256&objectid=10522985

[15] http://www.dailycamera.com/guest-opinions/ci_28283397/robert-f-kennedy-jr-doing-math-meningitis-vaccinations

[16] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086238/

[17] http://www.scoop.co.nz/stories/GE0710/S00127.htm

[18] http://www.nejm.org/doi/full/10.1056/NEJM200001203420319

[19] http://www.whale.to/vaccine/bolland.pdf

[20] http://aje.oxfordjournals.org/content/167/9/1140.long

[21] https://www.youtube.com/watch?v=SFQQOv-Oi6U (0:18:20-0:22:40)

[22] https://web.archive.org/web/20140822130818/http://tvnz.co.nz/view/page/1318360/1709217

[23] http://nces.ed.gov/fastfacts/display.asp?id=372

[24] http://www.nytimes.com/2004/10/27/health/panel-reviews-new-vaccine-that-could-be-controversial.html

[25] For Barbara Sumner Burstyn and Ron Law’s investigative journalism story of how the vaccine was adopted in New Zealand in spite of evidence of inefficacy, illegality, and more (http://www.scoop.co.nz/stories/HL0502/S00064.htm); and the government’s response to the published investigation (http://www.scoop.co.nz/stories/HL0505/S00352.htm). Following three years of Burstyn and Law’s investigative reporting, the Norwegian Minister of Health was forced to apologize for the damage caused by the vaccine (http://www.scoop.co.nz/stories/GE0710/S00127.htm).

[26] Shoenfeld, Y., Agmon-Levin, N., & Tomljenovic, L. (2015). Vaccines and Autoimmunity (pp. 185-190). Hoboke, NJ: Wiley Blackwell.

[27] http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/VaccineSafety/UCM096228#t1

[28] http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM308370.pdf

[29] http://www.fda.gov/downloads/BiologicBloodVaccines/Vaccines/ApprovedProducts/UCM131170.pdf

[30] http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM201349.pdf

[31] http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM431447.pdf

[32] http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM421139.pdf