More Resources

 

General information on Vaccines:

 

Information on Vaccine Exemption:

 

Advocacy for Free and Informed Consent:

 

Vaccine Risk/Benefits Analysis:

 

Information on Vaccine-Induced Autism:

 

Information on Vaccine Injuries from the vaccine for cervical cancer:

 

CDC Links:

 

Other related information:

Pertussis Vaccine Failure Should be a Wake-up Call

 

Whooping cough outbreaks have occurred with increasing frequency in the last year and are beginning to become major news items, as highlighted by major outbreaks on-going in California. In virtually every article, the disease is described as “vaccine preventable” and blame is often cast upon Jenny McCarthy and autism-crazed parents that frequently refuse vaccination. But the facts of the matter are not that simple.

Despite the recent press on the vaccine-autism debate, infant vaccination rates remain at or near all-time highs with 96.2% of infants getting at least three doses of DTaP in 2008 versus just 61% getting at least three doses of DTP in 1991 [1]. Furthermore, in recent outbreaks, a majority of affected have in fact been completely vaccinated (see NJ outbreak in which ALL affected children had been completely vaccinated). So given that the most at-risk population (children under 3 months) is not eligible for vaccination and their protection depends on the protection of older children, the real question to emerge from the recent pertussis outbreaks should be “Why is the pertussis vaccine no longer as effective or as long lasting as it once was?” People and public health agencies should be DEMANDING the answer to this question. They instead seem content with the possible addition of another booster of the DTaP to be given at seven years of age, thus increasing the number of doses of DTaP now given to American children to 6 and unnecessarily boosting tetanus and diphtheria in the bargain.

On a comical level, it is hard to imagine any other industry responding to the failure of their product by encouraging people to just buy more of the failing product. Do you want a second Toyota, just in case the first shoots off like a cannon? Yet this laughable marketing scheme seems to be just what Big Pharma has pulled off when it comes to DTaP. Their reward for a failing product is 20% higher sales of that very same product.

Historical Perspective

To fully understand the problems behind the failure of DTaP, we need a brief review of the history of pertussis vaccination. Use of the singular pertussis vaccine began in the US in the 1930s. By the 1940s, doctors and public health authorities switched to using DTP, a triple-vaccine designed to provide immunity against diphtheria, tetanus and pertussis. Overtime, however, a substantial number of adverse events resulting in permanent injury were found to be associated with the DTP vaccine (specifically the pertussis component), leading to the development of DTaP, which became available for use in 1991. The difference between the two vaccines is in the pertussis component. The previous (DTP) used “whole-cell pertussis” while the newer vaccine utilized “acellular pertussis” (hence the small a before the P in DTaP) which consists of selected purified pertussis antigens. Because of the lowered number of antigens presented, it is thought to have an increased safety profile and has demonstrated a substantial reduction in adverse events.

One could see why the whole-cell pertussis vaccine might be more effective in preventing pertussis disease than the acellular version. Quite simply, the whole-cell pertussis component more closely resembles actual infection with pertussis. Therefore, one could assume that the immune response generated by this challenge would be more effective in preventing natural infection. However, we need not rely on common sense alone, as the published scientific data confirms a key difference between the two vaccines.

Immunological Responses

The CDC reports that in the United States, cases of whooping cough have increased approximately 10-fold in the last twenty years [2], DESPITE AN INCREASE IN VACCINATION COVERAGE FROM 61% to 96%. Numerous papers suggest that the reason why is due to the inadequate type of immune response generated by the acellular pertussis vaccine versus the previous whole-cell pertussis. Protection against pertussis relies on both humoral immunity and on cellular Th1-type immune responses [3-9]. Seemingly of critical importance are recent studies showing that while the whole-cell pertussis generated a strong antigen-specific Th1 response, aP vaccines induced mixed Th1/Th2 responses in humans [9-12]. It is also important to note that at the time the aP vaccine component was introduced, the technology and know-how did not exist to compare these types of immune responses. However, now that this capability exists and given the apparent failure of the vaccine to illicit long lasting immunity, it seems crucial that public health authorities and vaccine manufacturers address this problem.

Aluminum Adjuvants

While the change in antigen presentation may be sufficient to cause the change in vaccine efficacy, there may be other possible explanations worth exploring as well. The first of these explanations centers on the use of aluminum adjuvants in many vaccines, including DTaP. Aluminum has been shown to preferentially generate a Th2-type response [13,14]. In recent years, the use of aluminum adjuvants that induce a strong Th2 response by a mechanism not yet fully understood has increasingly come under criticism by vaccine safety advocates, including Dr. Robert Sears, author of “The Vaccine Book”. Given the rapid rise of childhood chronic illness, such as allergies and asthma, that are mediated by Th2 responses, this criticism seems warranted and worthy of investigation. The use of adjuvants that stimulate a Th2 response in a vaccine for a disease that requires a Th1 response leads to a less effective vaccine that has a higher safety risk. Of course, back in the late 1980s the need for Th1 response for clearance of pertussis or the tendency of aluminum adjuvants to produce a Th2 response (while suppressing the Th1) was unknown and not yet on the scientific radar. But now these facts are known and are part of the mainstream published scientific literature. To continue this practice as if nothing is wrong is troubling. It is this kind of blindness to scientific fact that is causing concerned citizens to increasingly question the current vaccine paradigm.

Environmental Issues

Furthermore, a recent paper published in the journal Environmental Health Perspectives suggests that the failure of the pertussis vaccine may be the result of our increasingly toxic environment [15]. The study found that postnatal PCB exposure levels had an immunotoxic effect that limited the response to the DTaP vaccine. PCB exposure levels at 18 months of age were most predictive of lowered lasting immune response, including responses below what is considered clinically protective. This is suggestive of a crucial time period during early childhood for the proper development of the immune system. Children with higher PCB levels at age 18 months had a 1.64 odds ratio of not being able to generate clinically protective antibody levels at age seven. It may be that the immune systems of young children are so skewed either from toxic exposure or changes in the development of the immune system generated by the current vaccination schedule that no amount of booster shots with DTaP are going to adequately protect all children. If this is indeed the case, the future of fighting diseases may depend not solely on mass vaccination but rather on finding ways to maintain the proper function and balance of the immune system in this increasingly toxic world.

Regardless of the cause or causes, the increasing failure of the pertussis vaccine requires serious investigation. The unwillingness to honestly inquire about the nature of the failure (presumably because it might cast doubt on the use of aluminum adjuvants, our overall approach to the vaccine program and the safety of grandfathered in products in an ever-changing world) is just another of a long list of examples of the public health authorities refusing to support the vaccine program with adequate research. It is this kind of failure, not Jenny McCarthy, that has parents questioning the logic of the CDC, and many ultimately deciding that the unseen benefits do not outweigh the potential risks.

 

References:

[1] Guris D, Strebel P, Bardenheier B, Brennan M, Tachdjian R, Finch E, Wharton M, Livengood J. Changing Epidemeology of Pertussis in the United States: Increasing Reported Incidence Among Adolescents and Adults, 1990-1996. Clin Infect Diseases. 1998. 28: 1230-7.

[2] Centers for Disease Control and Prevention. Pertussis- United States; 2001-2003. Found at www.cdc.gov.

[3] Mills KHG, Barnard A, Watkins J, Redhead K. Cell-mediated immunity to Bordetella pertussis: role of Th1 cells in bacterial clearance in a murine respiratory infection model. Infect Immun 1993; 61(2): 399-410.

[4] Barbic J, Leef MF, Burns DL, Shahin RD. Role of gamma interferon in natural clearance of Bordetella pertussis infection. Infect Immun 1997; 65(12):4904-8.

[5] Redhead K, Watkin J, Barnard A, Mills KHG. Effective immunization against Bordetella pertussis respiratory infection in mice is dependent on induction of cell-mediated immunity. Infect Immun 1993; 61(8):3190-8.

[6] Leef M, Elkins KL, Barbic J, Shahin RD. Protective immunity to Bordetella pertussis requires both B cells and CD4+ T cells for key functions other than specific antibody production. J Exp Med 2000; 191(11):1841-52.

[7] Ryan M, Murphy G, Gothefors L, Nilsson L, Storsaeter J, Mills KH. Bordetella pertussis respiratory infection in children associated with preferential activation of type 1 T helper cells. J Infect Dis 1997;175(5): 1246-50.

[8] Mills KHG. Immunity to Bordetella pertussis. Microbes Infect 2001;3(8): 655-77.

[9] Dirix V, Verscheure V, Goetghebuer T, Hainaut M, Debrie A, Locht C, Mascar F. Cytokine and antibody profiles in 1-year-old children vaccinated with either acellular or whole-cell pertussis vaccine during infancy. Vaccine 2009; 27: 6042-47.

[10] Mascart F, Hainaut M, Peltier A, Verscheure V, Levy J, Locht C. Modulation of the infant immune response by the first pertussis vaccine administrations. Vaccine 2007; 25: 391-8.

[11] Ryan M, Murphy G, Ryan E, Nilsson L, Shackley F, Gothefors L et al. Distinct T-cell subtypes induced with whole cell pertussis and acellular pertussis vaccines in children. Immunology 1998; 93: 1-10.

[12] Ausiello CM, Urbani F, la Sala A, Lande R, Cassone A. Vaccine and antigen dependent type 1 and type 2 cytokine induction after primary vaccination of infancts with whole-cell or acellular pertussis vaccines in children. Infect Immun 1997; 65: 2168-74.

[13] Grun JL, Maurer P. Different T helper cell subsets elicited in mice utilizing two different adjuvant vehicles: the role of endogenous interleukin 1 in proliferative responses. Cell Immunol 1989 121: 134-145.

[14] Marrack P, McKee A, Munks M. Towards an understanding of the adjuvant action of aluminum. Nature Immunology. 2009 9: 287-293.

[15] Heilmann C, Jorgensen E, Nielsen F, Heinzow B, Weihe P, Grandjean P. Serum Concentration of antibodies against vaccine toxoids in children exposed perinatally to immunotoxicants. Environmental Health Perspectives. 2010.

The words “allergy” and “anaphylaxis” were created to describe vaccine-injury

 

The terms “allergy” and “anaphylaxis” were created following a strange illness that affected up to 50% of vaccinated children at the close of the 1800s.  This illness was simply called “serum sickness” and followed the first mass administration of diphtheria anti-toxin sera.  Austrian pediatrician Clemens von Pirquet studied the illness at length and observed that the symptoms of this sickness resembled those in people who were hypersensitive to pollens and bee stings.  To better describe this ‘altered reactivity’ to the sera he created the Latin derived word allergy in 1906.

In 1901, another doctor Charles Richet stumbled on the same phenomenon during attempts to vaccinate dogs to a jellyfish poison.  He began by injecting dogs with trace amounts of the poison to create a level of tolerance to it.  However, when he injected the animals a second time, he provoked a violent reaction that quickly killed the dogs.  For this reaction he used a Latin term ana-phylaxis or anti-protection, because the outcome was the opposite from the protection that the vaccine was supposed to provide.

Richet experimented further.  He quickly discovered that any protein including food proteins injected into the bloodstream results in sensitization and anaphylaxis on subsequent exposure to the food. Richet injected minute quantities of milk and meat proteins into cats, rabbits and horses and showed that anaphylaxis is a universal immune system defense.

Prior to the advent of vaccination, mass allergy such as serum sickness was unknown.  At the dawn of the 20th century, doctors identified the problem of allergy as an outcome of mass vaccination – on which government relied.  The dilemma of serum-induced allergy was summarized by allergist Warren Vaughan in 1941:

Serum disease, as this is called, is a man-made malady.  If we had no curative serums and if there were no such thing as a hypodermic syringe with which to introduce the material under the skin, there would be no serum disease.  Instead multitudes would still be dying from diphtheria and lockjaw … Thus, we find ourselves in somewhat of a dilemma, faced with the necessity for choosing the lesser of two potential evils. Warren Vaughan, Strange Malady (1941)

As vaccine ingredients became better refined to reduce the sensitizing proteins, prevalence of serum sickness decreased.  With the 20th century expansion of vaccination programs and schedules to include food proteins and adjuvants, however, other unforeseen problems arose to take its place.  One of these was peanut allergy (see The peanut allergy epidemic may have been precipitated by pediatric injections).  

Disease Risk – Varicella

 

Risk to a child from Varicella if not vaccinated until after the age of 5:

 

Incidence Rates:  Varicella vaccine was licensed in the United States in 1995. In the prevaccine era, varicella was endemic in the United States, and virtually all persons acquired varicella by adulthood. As a result, the number of cases occurring annually was estimated to approximate the birth cohort, or approximately 4 million per year.[1]  In 2008, varicella incidence in the United States was 29 cases per 100,000 population.[2]

Case Fatality Rate: In the 1 – 4 age group, deaths with Varicella as an underlying or contributing cause decreased from 18.4 per year in 1990 – 1994 to 2.0 in 1999 – 2001 [3].  Based on census data [4], the annual mortality rate in the 1-4 age group was 0.011 per 10,000 population (1 in 874,000) in 1990 – 1994 and 0.001 per 10,000 (1 in 7, 726,000) in 1999 – 2001.

Rate of Long Term Sequelae or Injury: The proportion of hospitalizations with complications ranged from 51% – 54% from 1993 – 1995, and from 39% – 54% from 1996 – 2001 [3].  Permanent sequelae from varicella is rare, and numbers were not found.  For the purposes of this analysis, it is assumed that 2% of varicella hospitalizations with complications result in permanent injury for children ages 1-4.  Based on census data [4], the annual permanent-injury rate in the 1-4 age group was 0.84 per 10,000 population (1 in 119,000) in 1993 – 1995 and 0.012 per 10,000 (1 in 813,000) in 2001.

Incremental Risk in Population with Low Rates of Vaccination (if a child does not vaccinate by age 5): Varicella risk to children less than one year old excluded from the incremental risk analysis since they are not eligible for vaccination under the current guidelines.  The incremental cumulative risk of varicella permanent-injury to a child not vaccinated by age five was calculated to be 0.13 per 10,000 or 1 in 74,000.  The cumulative risk of death was calculated to be 0.046 per 10,000 or 1 in 218,000.

Incremental Risk in Highly Vaccinated Population (if a child does not vaccinate by age 5): This analysis utilizes the vaccination coverage rate in 1999 – 2001 [5], and assumes that all varicella permanent-injuries and deaths in 2001 occurred to unvaccinated children. Varicella risk to children less than one year old excluded from the incremental risk analysis since they are not eligible for vaccination under the current guidelines.  The incremental cumulative risk of varicella permanent-injury to a child not vaccinated by age five was calculated to be 0.019 per 10,000 or 1 in 408,000.  The cumulative risk of death was calculated to be 0.0052 per 10,000 or 1 in 1,931,000.

 

References:

[1] Centers for Disease Control and Prevention: Epidemiology and Prevention of Vaccine-Preventable Disease. Atkinson W, Wolfe S, Hamborsky J, McIntyre L. eds. 11th edition. Washington D.C.: Public Health Foundation, 2009.

[2] http://cdc.confex.com/cdc/nic2010/webprogram/Paper22595.html

[3] Centers for Disease Control and Prevention. Nguyen, H., Jumaan, A., Seward, J. Decline in Mortality Due to Varicella after Implementation of Varicella Vaccination in the United States.  NEJM 2005;352: 450-8

[4] United States Census Bureau. The 2010 Statistical Abstract; Table 78: Live Births, Deaths, Marriages and Divorces: 1960 to 2007.

[5] Davis MM, Patel MS, Gebremariam A. Decline in varicella-related hospitalizations and expenditures for children and adults after introduction of varicella vaccine in the United States. Pediatrics 2004;114:786–92.

Disease Risk – Tetanus

 

Risk to a child from Tetanus if not vaccinated until after the age of 5:

Tetanus is an infectious disease caused by contamination of wounds from bacteria that live in the soil. Tetanus spores are found throughout the environment, usually in soil, dust, and animal waste. Tetanus is acquired through contact with environment; it is not transmitted from person to person. Tetanus results in severe, uncontrollable muscle spasms. In severe cases, the muscles used to breathe can spasm, causing a lack of oxygen to the brain and other organs that may possibly lead to death. Neonatal tetanus is similar to generalized tetanus except that it affects a baby that is less than 1 month old [1].  Tetanus is almost fully preventable with proper injury treatment.

Although tetanus still is a very serious disease, the prognosis with modern techniques of intensive care is markedly better than that predicted by earlier statistics.  With appropriate intensive care, the ultimate mortality rate of tetanus in the United States has been reduced greatly. The overall case-fatality rate in the United States has declined from 91% in 1947, to 24% during 1989 to 1991, to 11% during 1995 to 1997.  No mortality was observed in the United States between 1995 and 1997 in individuals younger than 25 years of age. Survivors are left largely without sequelae of tetanus [2].  Among all ages during 1998-2000, 130 cases were reported with 20 deaths; all reported deaths occurred among patients aged 33-88, with 75% (15/20) of the deaths in patients aged 60 and older [3].

Case Fatality Rate: Age plays an important part in outcome, with only 5% mortality rate for patients younger than 50 years of age, as compared to 42% for those older than 50. For the purposes of this analysis, we use the 5% case mortality rate in tetanus cases due to acute injury [2].

Rate of Long Term Sequelae or Injury: Tetanus due to acute injury or wounds can be appropriately managed medically with antibiotics to kill the bacteria, tetanus booster shot if necessary, and occasionally antitoxin to neutralize the toxin [1]; survivors are left largely without sequelae of tetanus [2].  For the purposes of this analysis, we use a 0% case sequelae rate in tetanus cases due to acute injury.

Incidence Rates:  In the United States, the average annual incidence of tetanus during 1998–2000 was 0.05 cases per million population among persons aged <20 years [3].  In 1947 through 1949, before widespread use of the vaccine, an average of 580 cases of tetanus and an average of 472 deaths from tetanus were reported [5].  During 1972–2006, the cumulative number of reported neonatal tetanus cases decreased to 32; the most recent cases were reported in 1989, 1995, 1998, and 2001.[4]

Incremental Risk in Population with Low Rates of Vaccination (if a child does not vaccinate by age 5):

Tetanus is not contagious from person to person [1].  Instead, the risk to a child under age 5 consists of a) the risk of neonatal tetanus and b) risk of tetanus from acute injury.

Since a child is not vaccinated for tetanus until ages 2, 4, and 6 months, the vaccination status of the child does not affect the risk of neonatal tetanus so the incremental risk of neonatal tetanus from the child not vaccinating is zero.

The risk to a child from tetanus due to acute injury is based upon the risk of an acute injury and whether the child is vaccinated.  To determine the average risk of an unvaccinated child contracting tetanus from an acute injury, we utilized the reported tetanus cases in the pre-vaccine era (1947 – 1949) of 580 cases per year [5] and assumed 75% of cases were reported to calculate an estimated tetanus incidence rate per year amongst unvaccinated individuals in the USA of 0.05 per 10,000 or 1 in 190,000.  The cumulative risk of death from tetanus due to acute injury up to age 5 was calculated to be 0.013 per 10,000 or 1 in 759,000.  The cumulative risk of permanent injury from tetanus due to acute injury was calculated to be 0.00 per 10,000, since those who survive do not generally have permanent sequelae [2].  Since tetanus is rare amongst vaccinated individuals, all of this calculated risk is considered to be incremental risk incurred due to the hypothetical decision that a child does not vaccinate until age 5.

Incremental Risk in Highly Vaccinated Population (if a child does not vaccinate by age 5): Tetanus is not transmitted from person to person.  Therefore, the risks to a child who does not vaccinate by age 5 are the same when children in the population are highly vaccinated as the risks when children in the population have low rates of vaccination (see analysis above).

Note: This analysis analyzes the risks based upon a hypothetical decision for a child to not vaccinate until age 5.  Although there is an increased risk to that hypothetical child of neonatal tetanus if the mother is not fully vaccinated for tetanus, the decision of the mother to vaccinate prior or during child-bearing years was deemed not in scope for this analysis.

 

References:

[1] Tetanus article on eMedicineHealth: http://www.emedicinehealth.com/tetanus/article_em.htm

[2] Oski’s Pediatrics: Principles & Practice.  By Julia A. McMillan, Ralph D. Feigin, Catherine DeAngelis, M. Douglas Jones.  2006. page 1033.

[3] Centers for Disease Control and Prevention:  Tetanus Surveillance – United States, 1998-2000.  MMWR, Surveillance Summaries, June 20, 2003 / 52 (S S03);1-8

[4] Centers for Disease Control and Prevention:  Prevention of Pertussis, Tetanus, and Diphtheria Among Pregnant and Postpartum Women and Their Infants. MMWR, Recommendations and Reports, May 30, 2008 / 57 (04);1-47, 51

[5] http://www.cdc.gov/vaccines/vpd-vac/tetanus/downloads/dis-tetanus-bw-office.pdf

[6] Okoromah CAN, Lesi FEA .  Diazepam for treating tetanus. 2004. http://www.nichd.nih.gov/cochrane/okoromah/okoromah.htm#Background

[7] P Teknetzi, S Manios, and V Katsouyanopoulos. Neonatal tetanus—long-term residual handicaps. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1628125/pdf/archdisch00750-0076.pdf

[8] http://www.census.gov/popest/archives/1990s/popclockest.txt

 

Disease Risk – Rubella

 

Risk to a child from Rubella if not vaccinated until after the age of 5:

According to the CDC [1]:

  • Rubella infection during pregnancy can lead to miscarriage, stillbirth, premature delivery, and birth defects. The danger is highest for women who get rubella during the first 12 weeks of pregnancy. Birth defects caused by rubella include deafness, cataracts, and heart defects. Babies also may have mental retardation. This group of health problems is called Congenital Rubella Syndrome (CRS) [1]
  • Rubella almost never causes serious illness or complications in infants and young children [1]
  • The prevention of Congenital Rubella Syndrome (CRS) is the main objective of the rubella vaccination programs in the United States [1]
  • The first rubella vaccines were licensed in 1969 [2]

Before licensing of the live attenuated vaccine in 1969, rubella in the United States was primarily a disease of school-aged children, with a peak incidence in children aged 5-9 years [3]. Following widespread use of rubella vaccine in children, peak incidence has shifted to persons older than 20 years, who comprise 62% of cases of rubella reported in the United States [3].

Incidence Rates:  Since rubella and congenital rubella syndrome became nationally notifiable diseases in 1966, the largest annual total of cases of rubella reported in the United States was in 1969 when 57,686 cases were reported (58 cases per 100,000 population) with 29 deaths and 31 cases of CRS [2][3].  From 2004 – 2008 an average of 12 cases of rubella were reported per year in the United States [4].  Previously the peak age group for infection was 5 -9 year olds, but since the introduction of the vaccine adults now comprise the largest group [2].

Case Fatality Rate: In 1969, the year with the largest annual total of cases since rubella became a nationally notifiable disease in 1966, there were 57,686 cases reported with 29 deaths and 31 cases of CRS [3].  For the purposes of this analysis, a case fatality rate of 29 / 57,686 or 0.0005 was used.

Rate of Long Term Sequelae or Injury: Rubella almost never causes serious illness or complications in infants and young children [1]. Infection in younger children is characterized by mild constitutional symptoms and rash [3]. Complications of rubella are not common, but they gener­ally occur more often in adults than in children [2].  Encephalitis occurs in one in 6,000 cases, more frequently in adults (especially in females) than in children [2].  Permanent sequelae from rubella is very rare, and there are no figures available [7][8][9].  For the purposes of this analysis, it is assumed that 5% of rubella encephalitis cases result in permanent injury.

Incremental Risk in Population with Low Rates of Vaccination (if a child does not vaccinate by age 5): Rubella almost never causes serious illness or complications in infants and young children, so the prevention of Congenital Rubella Syndrome (CRS) is the main objective of the rubella vaccination programs in the United States [1]. The rubella vaccine is administered after the age of 12 months, and thus confers no protection against CRS for the child being vaccinated; instead, children are vaccinated to minimize the risk of CRS to unborn children.  The vaccination status of the child does not affect the risk of CRS to that child; therefore, the incremental risk of CRS from that child choosing to not vaccinate would be zero.

The risk of death from rubella to the unvaccinated child is extremely low.  Assuming 75% of cases were reported in 1969, and assuming an equivalent risk of death and permanent injury across all age groups, the cumulative risk of death in the first five years of life to a child who does not vaccinate was calculated to be 0.0095 per 10,000 or 1 in 1,048,329.  The cumulative risk of permanent injury was calculated to be 0.00016 per 10,000 or 1 in 63,242,121.

Incremental Risk in Highly Vaccinated Population (if a child does not vaccinate by age 5): From 2004 – 2008 an average of 12 cases of rubella were reported per year in the United States [4].  No deaths or permanent injuries were reported.  The cumulative risk of death and permanent injury in the first five years of life to a child who does not vaccinate was calculated to be zero.

 

 

 

References:

[1] Centers for Disease Control and Prevention. Diseases and the Vaccines that Prevent Them: Rubella.   http://www.cdc.gov/vaccines/vpd-vac/rubella/downloads/dis-rubella-bw-office.pdf

[2] Centers for Disease Control and Prevention: Epidemiology and Prevention of Vaccine-Preventable Disease. Atkinson W, Wolfe S, Hamborsky J, McIntyre L. eds. 11th edition. Washington D.C.: Public Health Foundation, 2009.  {a.k.a. “The Pink Book”}  http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/rubella.pdf

[3] EMedicine. Pediatric Rubella. http://emedicine.medscape.com/article/968523-overview#a0199

[4] Center for Disease Control and Prevention.  Notifiable Diseases/Deaths in Selected Cities Weekly Information.  MMWR2009; 58(45): 1276-1287.

[5] http://www.infoplease.com/ipa/A0005067.html

[6] http://www.census.gov/popest/archives/1990s/popclockest.txt

[7] Cantwell, RJ. Rubella Encephalitis. Br Med J. 1957 December 21; 2(5059): 1471–1473. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1962912/?page=1

[8] KK Lau, ST Lai, JY Lai, WW Yan, TMK So, TY Wong. Acute Encephalitis Complicating Rubella.  HKMJ, September 1998. Vol 4, No 3. http://sunzi.lib.hku.hk/hkjo/view/22/2200435.pdf

[9] Sherman, FE, Michaels, RH, and Kenny, FM. Acute Encephalopathy (Encephalitis) Complicating Rubella. JAMA, May 24, 1965. Vol 192, No. 8. http://jama.ama-assn.org/content/192/8/675.full.pdf+html

Disease Risk – Rotavirus

 

Risk to a child from Rotavirus if not vaccinated until after the age of 5: 

Case Fatality Rate: Rotavirus causes diarrhea, which in developed countries with modern medical facilities can typically be managed medically without complication.  From 1993 to 2003, the estimated number of deaths per year in the United States in children under five from rotovirus was 37 [1].

Rate of Long Term Sequelae or Injury: There are no permanent injuries due to rotavirus infections.

Incidence Rates:  Unless children are vaccinated, almost all of them get rotavirus before their 5th birthday, however complication are rare [2]. 

Incremental Risk in Population with Low Rates of Vaccination (if a child does not vaccinate by age 5): Based on the 37 deaths per year 1993 to 2003 [1] prior to the implementation of the vaccine, the cumulative risk of death in first five years of life if a child does not vaccinate was calculated to be 0.09 deaths per 10,000 or 1 in 108,100.

Incremental Risk in Highly Vaccinated Population (if a child does not vaccinate by age 5): The Rotashield vaccine was introduced in 1998 and subsequently withdrawn in 1999.  The Rotateq vaccine was approved in 2006, and the Rotarix vaccine was approved in 2008.  There is not yet enough data following its implementation, nor are there high enough vaccination coverage rates, to assess whether there will be a herd immunity effect that would reduce the risk to an unvaccinated child [3].  Thus for this analysis, the incremental risk is assumed to be the equivalent in both analysis cases (highly-vaccinated population and population with low rates of vaccination). 

References:

[1] Kølsen Fischer,T., Viboud, C., Parashar, U., Malek, M, Steiner, C., Glass, R., Simonsen, R.  Hospitalizations and Deaths from Diarrhea and Rotavirus among Children <5 Years of Age in the United States, 1993–2003.

[2] Centers for Disease Control and Prevention.  Diseases and the Vaccines that Prevent them: Rotavirus.  http://www.cdc.gov/vaccines/vpd-vac/rotavirus/downloads/dis-rotavirus-color-office.pdf

[3] Tate, JE et al. Uptake, Impact, and Effectiveness of Rotavirus Vaccination in the United States: Review of the First 3 Years of Postlicensure Data.   Pediatric Infectious Disease Journal: January 2011 – Volume 30 – Issue 1 – pp S56-S60doi: 10.1097/INF.0b013e3181fefdc0

 

Disease Risk – Polio

 

Risk to a child from Polio if not vaccinated until after the age of 5:

Polio is an infectious disease caused by a virus that infects the throat and intestinal tract. It is most often spread through person-to-person contact with the stool of an infected person, and may also be spread through oral/nasal secretions. The polio vaccine was introduced in 1955 [3].

Wild-type polio has not been eradicated in four countries:  Nigeria, Pakistan, Afghanistan, and India (most of India is polio-free; persistent transmission of poliovirus is localized in areas of western Uttar Pradesh and central Bihar), with a further four countries known to have (Angola, Chad and Democratic Republic of the Congo) or suspected of having (Sudan) re-established transmission of poliovirus [1].

Rate of Long Term Sequelae or Injury: Up to 95% of all polio infections are asymp­tomatic. Estimates of the ratio of asymptomatic to paralytic illness vary from 50:1 to 1,000:1 (usually 200:1, or 0.5%). Many persons with paralytic poliomyelitis recover completely and, in most, muscle function returns to some degree. Weakness or paralysis still present 12 months after onset is usually permanent.[2]

Incidence Rates:  In the immediate pre-vaccine era, improved sanitation allowed less frequent exposure and increased the age of primary infection. Boosting of immunity from natural exposure became more infrequent and the number of susceptible persons accumulated, ultimately resulting in the occurrence of epidemics, with 13,000 to 20,000 para­lytic cases reported annually [2].  For the purposes of this analysis, the incidence rate of paralytic polio in the pre-vaccine era was calculated to be a midpoint of 16,500 annual cases divided by the average population in the years 1950 – 1955 [4], which equates to 1.04 per 10,000 or 1 in 9,586.

Polio was eradicated from the United State in 1979, and from the Western hemisphere in 1991.  From 1980 through 1999, there were 152 confirmed cases of paralytic polio reported in the USA.  Of the 152 cases, 6 cases were imported from outside the USA, 2 were indeterminate, and the remaining 144 cases were vaccine-induced polio from the Oral Polio Vaccine (OPV).  OPV was replaced in the USA by the Inactivated Polio Vaccine (IPV) in 2000.  In 2009, only 1,579 confirmed cases of polio were reported globally and polio was endemic in four countries.[2]  Vaccine-induced polio is no longer a risk in the USA since the OPV has not been used there since 2000.  For the purposes of this analysis, the incidence rate of paralytic polio in the post-vaccine era was calculated to be the average cases per year in 1980 – 1999 (8/20) divided by the average USA population in that time period [4], resulting in a 0.000016 per 10,000 or 1 in 623,000,000.

Case Fatality Rate: The death-to-case ratio for paralytic polio is generally 2%–5% among children. [2].

Incremental Risk in Population with Low Rates of Vaccination (if a child does not vaccinate by age 5):

Assuming that polio would travel from one of the four endemic countries to the USA and reach similar incidence levels as in the pre-vaccine era, the cumulative risk of paralytic polio in the first five years of life to an unvaccinated child was calculated to be 5.2 per 10,000 or 1 in 1,918.  The cumulative risk of death was calculated to be 0.18 per 10,000 or 1 in 54,776.

Incremental Risk in Highly Vaccinated Population (if a child does not vaccinate by age 5):  

The cumulative risk of paralytic polio in the first five years of life to an unvaccinated child was calculated to be 0.00008 per 10,000 or 1 in 125 million.  The cumulative risk of death was calculated to be 0.000003 per 10,000 or 1 in 3.6 billion.

 

 

References:

[1] Global Polio Eradication Initiative.  http://www.cdc.gov/vaccines/vpd-vac/polio/dis-faqs.htm

[2] Centers for Disease Control and Prevention: Epidemiology and Prevention of Vaccine-Preventable Disease. Atkinson W, Wolfe S, Hamborsky J, McIntyre L. eds. 11th edition. Washington D.C.: Public Health Foundation, 2009.

[3] Centers for Disease Control and Prevention: Polio Disease – Questions and Answers.  http://www.cdc.gov/vaccines/vpd-vac/polio/dis-faqs.htm

[4] http://www.census.gov/popest/archives/1990s/popclockest.txt

 

Disease Risk – Pertussis

 

Risk to a child from Pertussis if not vaccinated until the age of 5:

Pertussis, also known as whooping cough, is a highly contagious bacterial disease caused by Bordetella pertussis.  It’s characterized by severe coughing spells that end in a “whooping” sound when the person breathes in.  Historically, pertussis caused significant morbidity and mortality in the world.  In the 1940’s in the US, pertussis was responsible for more infant deaths than measles, scarlet fever, diphtheria, polio, and meningitis combined.[1]

Routine pertussis immunization got underway in the United Stated in the 1940’s and mass pediatric vaccination has been successful in significantly reducing both the morbidity and mortality of Pertussis.  Unfortunately, pertussis vaccination was also associated with high rates of adverse reactions related to severe neurologic disease and death.[2]  Although pediatric vaccination for pertussis has demonstrated the ability to protect unvaccinated infants < 6 months of age through herd immunity, pertussis is still endemic in highly vaccinated populations worldwide.  Despite high rates of immunization, cyclical outbreaks of pertussis in children < 5 still occur as documented by Fine and Clarkson [3].  Cherry suggests that this indicates that immunization controls disease but does not control the prevalence of the organism in the population.[4]

Due to a variety of reasons, both Japan and Sweden eliminated their pediatric pertussis vaccination programs in relatively recent times (Japan between 1975-1981, Sweden between 1979-1995).  Both countries re-instituted pediatric vaccination using newer vaccines with less adverse reactions.

Factors Not Considered: There is considerable evidence that the risk from severe pertussis disease is highly variable depending on factors influenced by economic and living conditions.  Morbidity and mortality due to pertussis is far higher in the developing world.  In a study from the UK, Maclure found that the risk of hospitalization from pertussis in children living in deprived households was almost 10 times higher than in areas where households were not deprived.[5]  For pertussis, overcrowding and unemployment were more correlated with pertussis hospitalization than vaccination rates.[5]  In the United States today, pertussis rates are highly correlated to race/ethnicity.  The reasons for the correlation are unknown although several hypotheses include the factors of living conditions and access to health care [6-8].

Case Fatality Rate: Medical treatment and modern living conditions have drastically reduced the rates of both morbidity and mortality from pertussis over time.  As described by Romanus [9], the fatality rate in major outbreaks in both Swedish and England and Wales outbreaks (1977-1979 for England and Wales, 1981-1983 for Sweden) remained low.  Cherry [2] makes a case that the England and Wales deaths were underreported during the 1977-1979 epidemic.  However, the experience from Sweden provides the most relevant information because they had the longest period of an unvaccinated population (17 years) in recent times.  The tracking of the disease in Sweden has been quite rigorous compared to other countries and during their period of non-vaccination, they instituted modern medical protocols to treat the disease including aggressive antibiotic treatment and post-exposure prophylaxis for infants below 6 months. [10]  Romanus documents only 3 fatalities over a 3 year period in Sweden (1981-1983 a period of highly endemic pertussis in Sweden).  Two of the cases were in children older than 5 years with severe congenital disease and the third was only 4 months old.[9]  Due to the extremely low number of fatalities in Sweden during the period of vaccination, this analysis can’t derive a usable case fatality rate from Sweden.

In the US, all of the recent deaths (9) from the epidemic in the highly vaccinated California population occurred in infants < 2 months and thus were not vaccine preventable.[6]  Kanai documents that in 1977 (during the period when Japan stopped vaccinating), 14 of 19  deaths (74%) occurred in infants 2 months old or less,  17 of 19 were < 6 months old (89%) and the remaining deaths all occurred in infants < 1 year old.[11]  These statistics illustrate that in modern times (in populations that have both high or low levels of vaccination), pertussis vaccination does not directly provide a significant reduction to risk of death for the individual since the vast majority of the risks to infants are at an age prior to vaccination.  The vast majority of the reduction in pertussis fatalities in highly vaccinated populations is due to reduced pediatric disease circulation and the resulting herd immunity protecting the vulnerable infant population.  This analysis is focusing on the individual incremental risk of death due to lack of vaccination.  The statistics from Kanai show us that only 11% of the deaths in infants < 1 year of age were vaccine preventable given the age distribution of deaths.  This is consistent with the notion that infants < 6 months account for the vast majority of serious and subsequently fatal cases of pertussis in both vaccinated and unvaccinated populations.  The risk to infants < 6 months has changed from historical times because prior to universal vaccination, infants < 6 months would have been maternally protected if they were breast fed.  However, it would likely require at least two decades of non-vaccination for this lost pattern to re-emerge – the length of time for unvaccinated females to bear children.  This analysis will base the incremental fatality ratio on the average US case fatality rate of 1% from Cherry [2]. The vaccine preventable case fatality rate used will be 0.11% of incidence from 0-1 year and 0 for all other ages.  The case fatality rate for children between 6-12 months of age is therefore estimated to be 0.22%.

Rate of Long Term Sequelae: According to Cherry [12], pertussis is a unique illness in that systemic manifestations are rare.  Cherry hypothesizes that the neurological symptoms of convulsions and encephalopathy are most likely caused by anoxia resulting from respiratory damage.  Pertussis epidemics can cause significant morbidity and hospitalizations in children < 5 years of age.  The Romanus study[9] documented around 18% of the hospitalized cases suffered neurologic or serious secondary sequelae or infection.  Although long term follow-ups were not directly studied by Romanus in Sweden[9], the study makes the following comment about the hospitalized cases:  “However, it is on record that all the surviving patients were apparently healthy on leaving the hospital and at the next visit.”[9]  An analysis of hospitalizations in Sweden (unvaccinated) illustrates again the vast majority of severe cases of pertussis (90%) occur in children < 5 years, with almost half (48%) occurring in infants < 1 year of age.[9]    Cherry [2] paints a more skewed picture in the US (a vaccinated population) with 67% of hospitalizations occurring in infants < 6 months of age.  None of the large studies of pertussis reviewed in this analysis provide any statistics of long term sequelae.  The few references found were all in infants < 6 months of age which is consistent with the repeated observation that severe disease is associated with the children in that age group.  Cherry indicates that long term sequelae does occur in encephalitis cases, but the reference is not from recent times.  The data from Cherry et al [12] also indicates that the majority of encephalitis cases were in children < 6 months of age.  Given the lack of evidence for long term sequelae in children over 6 months of age in the modern age, this analysis assumes an incremental risk for non-vaccination of 0.

Incremental Risk in Population with Low Rates of Vaccination (if a child does not vaccinate by age 5): The most modern statistics from an unvaccinated population comes from Sweden between 1979-1995.  From the analysis above, the mortality risk from Pertussis occurs in infants < 1 year of age.  This analysis takes the average incidence over 5 years around a peak year 1991 (1989-1993).[10]  Applying the case fatality rate of 0.11% against an average incidence of 914 per 100,000 yields a fatality rate of 1.006 per 100,000 or 1 in 99,375. 

Note: The theoretical case fatality rate for the US in unvaccinated populations is higher than it should be.  The data from Sweden [9] documents a total case fatality rate of 1 death per year or 1 per 90,000 over three years of outbreaks.  However, none of those deaths in Sweden were vaccine preventable.  This means that the vaccine preventable case fatality rate in unvaccinated Sweden was actually far lower.  This could be due to several factors including:  living conditions in the US differ from Sweden, medical protocol or care is better in Sweden than the US, or the 1% case fatality rate for the US is an overestimate in the modern era.  This analysis will use the calculated rate from above and it should be treated as an upper bound.

Incremental Risk in Highly Vaccinated Population (if a child does not vaccinate by age 5): Calculations of vaccine preventable risk are very difficult in highly vaccinated populations due to the lack of good statistics regarding vaccinated population counts, and percentage of vaccinated incidence.  As described above, in the case of pertussis, the reduction of deaths is almost entirely due to herd immunity.  If we review the historical epidemiological data from Cherry[12], the case fatality rate has dropped to approximately 1% of its previous historical value, largely paralleling the drop in pertussis incidence.  Taking 1% of the risk from populations with low rates of vaccination, yields a fatality rate of 0.01006 per 100,000 or 1 in 9,930,000.

 

References:

[1] Gordon JE, Hood HI: Whooping cough and its epidemiological anomalies.  AmJ Med Sci 1951; 222:333-361

[2] Cherry JD, Baraff LJ, Hewlett E: The past, present, and future of pertussis. The role of adults in epidemiology and future control.  West J Med. 1989 Mar;150(3):319-28.

[3] Fine PEM, Clarkson JA.  The recurrence of whooping cough:  possible implications for assessment of vaccine efficacy.  Lancet 1982;1:666-9.

[4] Cherry JD:  Historical Review of Pertussis and the Classical Vaccine.  J Infect Dis 1996 Nov;174 Suppl 3:S259-63

[5] Maclure A, Stewart GT.  Admission of children to hospitals in Glasgow: relation to unemployment and other deprivation variables.  Lancet 1984 Sep 22;2(8404):682-5.

[6] Pertussis Report, January 7, 2011.  California Department of Public Health

[7] Melnick M.  California’s Whooping Cough Epidemic Hits Latino Babies Hardest.  Time Healthland, Friday October 29, 2010.  http://healthland.time.com/2010/10/29/californias-whooping-cough-epidemic-hits latino-babies-hardest/

[8] Ostrov BF.  Whooping Cough (Pertussis) Epidemic in California:  Tips for Convering the Story.  Barbara Feder Ostrov’s Helath Jounalism Blog.  http://www.reportingonhealth.org/blogs/whooping-cough-pertussis-epidemic-california-tips-covering-story

[9] Romanus V, Jonsell R, Berqquist SO.  Pertussis in Sweden after the cessation of general immunization in 1979.  Pediatr Infect Dis J. 1987 Apr;6(4):364-71.

[10] ELEVEN YEAR REPORT Pertussis surveillance in Sweden Progress Report October 1, 1997 with an executive summary.  SMITTSKYDDSINSTITUTETS RAPPORTSERIE NR 6:2009

[11] Kanai K.  Japan’s experience in pertussis epidemiology and vaccination in the past thirty years.  Jpn J Med Sci Biol. 1980 Jun;33(3):107-43.

[12] Cherry JD, Brunell PA, Golden GS, Darzon DT. Report of the task force on pertussis and pertussis immunization–1988. Pediatrics 1988; 81(suppl):939-84.

 

Disease Risk – Pneumococcal disease

 

Risk to a child from Pneumococcal disease if not vaccinated until after the age of 5:

Streptococcus pneumoniae, also called pneumococcus, can cause invasive pneumococcal diseases (IPD) such as pneumonia and meningitis.  90 serotypes have been identified [1].  The PCV-7 pneumococcal conjugate vaccine (brand name “Prevnar”) was licensed in 2000 to target 7 serotypes of pneumococcus [1].  Pneumococcal serotypes compete with each other.  The introduction of the vaccine has decreased the incidence of IPD from the 7 serotypes targeted by the vaccine but conversely has increased IPD from non-vaccine pneumococcal serotypes.

Pneumococcal serotypes also compete with Hib, Staphylococcus aureus (“staph”), and other bacteria in the nasal passages which can be carried on an asymptomatic basis.  A study found that a reduction in vaccine-targeted pneumococcal serotypes is associated with an increase in staph [2].  Other studies found an increase in staph-related ear infections associated with the PCV-7 vaccine [3] [4].  One study discusses whether the current increase in severe community-acquired staph infections (MRSA, “Methicillin-resistant Staphylococcus aureus”) is partially caused by the introduction of the PCV-7 vaccine, and states that the answer is yet to be determined [3].  There is inter-species competition between pneumococcus and Hib [5], and a recent study have shown increases in the proportion of Hib and Moraxella catarrhalis bacteria in the middle-ear fluid of PCV7-immunized children [6].

 

Factors Not Considered: PCV-13 was licensed in 2010 to target 13 pneumococcal serotypes.  It is unclear whether it will result in other non-targeted pneumococcal serotypes to become more invasive, as was the experience with the PCV-7 vaccine [7].  There is also the potential that the PCV-13 vaccine may further increase staph and Hib colonization in nasal passages. It is too early to assess the incremental disease risk if not vaccinated with PCV-13, so this analysis only addresses incremental risk if not vaccinated with the PCV-7 vaccine.

Incidence Rates: After just a few years in the American market, initial studies of Prevnar’s impact [7][8] reported reductions of more than 60% in IPD cases and hospitalizations in children by 2004. The annual rate of hospitalization for invasive pneumococcal disease among children <5 years decreased from an average of 27.2 admissions/100,000 population during 1998–1999 to 10.1 admissions/100,000 population in 2004 [7]

However after an initial drop, the incidence rate stabilized and then began increasing as nonvaccine serotypes became more prolific.  Studies in Massachusetts [8][9][10] indicates that IPD (invasive pneumococcal disease) per 100,000 children under age 5 dropped from 53.1 in 1991 in the pre-vaccine era to 19.0 in 2001-2002 after the vaccine was fully implemented, but then increased to 24.8 in 2006-2007.  IPD from vaccine serotypes decreased to zero in 2006-2007, but IPD from non-vaccine serotypes increased to the 24.8 per 100,000 incidence rate.  The study covering the 2001-2007 years discussed that “Although we have learned that IPD incidence has stabilized in the PCV7 era, continued surveillance is necessary to learn whether the overall incidence of IPD in Massachusetts children is increasing. Incidence of disease caused by PCV7 serotypes has reached zero but overall incidence of IPD might increase if incidence of IPD caused by non-PCV7 serotypes continues to escalate.”[9].

Recent studies in Dallas [11] and Cleveland (Jacobs et al, 2008) [12] also indicate that incidence rates are rising due to nonvaccine serotypes.  Dallas rates of IPD in children fell by more than half from 1998 to 2003, but as the non-vaccine strains emerged, the overall IPD rate began increasing and reached three quarters of the pre-Prevnar rate by 2008. The Cleveland study showed growth rates from 100% to as high as 900% in the non-vaccine serotypes over a seven year period.

Mortality Rates: Despite the changes in incidence rate, overall mortality rate in children has not changed from the pre-vaccine era to the post-vaccine era.  In the most comprehensive investigation, one that covered a population of 19 million people in and around 8 major cities before and after the introduction of the PCV-7 vaccine, the study found that “the overall mortality rate among children did not change during the study period”.  The decrease in mortality rate due to vaccine serotypes was completely offset by the increased mortality rate due to nonvaccine serotypes.  The case fatality rate for children aged < 5 years increased both for disease due to vaccine serotypes and for disease due to nonvaccine serotypes, thus offsetting the reduction in incidence rates and keeping the mortality rate constant at 0.6 deaths per 100,000 children.[7]

Rates of Long Term Sequelae or Injury: Pneumococcal meningitis dropped from 3.6 per 100,000 children < age 5 in 1991 to an average of 1.3 in 2001-2003, but has since remained consistent through 2006-2007 [8][9][10].  According to a study in Massachusetts over the 2001-2007 study period, there were no significant changes in the proportion of IPD attributable to pneumonia, meningitis, bacteremia associated with upper respiratory tract infection, and bacteremia without focus.[9]

Long-term sequelae from pneumococcus include hearing loss, neurological deficit, mental retardation, seizure disorder, and motor deficits. The long-term sequelae rate ranges in studies from 36% in The Netherlands [13], 41% in Denmark [14], 52.6% in Taiwan [15], to 49% in Bangladesh [16].  For the purposes of this analysis, the average of those four percentages (45%) will be used.

Incremental Risk in Population with Low Rates of Vaccination (if a child does not vaccinate by age 5): The mortality rate of 0.6 per 100,000 children under age 5 has remained constant from the pre-vaccine era to the post-vaccine era.  Therefore, the incremental risk of death if not vaccinated until age 5 is zero.  The pneumococcal meningitis incidence rate per 100,000 children under age 5 in the pre-vaccine era and post-vaccine era was 3.6 and 1.3, respectively.  Using an average percentage of long-term sequelae of 45%, the cumulative incremental risk of permanent injury if not vaccinated until age 5 is 0.51 per 10,000 or 1 in 19,500.

Incremental Risk in Highly Vaccinated Population (if a child does not vaccinate by age 5): The mortality rate of 0.6 per 100,000 children under age 5 has remained constant from the pre-vaccine era to the post-vaccine era.  Therefore, the incremental risk of death if not vaccinated until age 5 is zero.  The pneumococcal meningitis incidence rate of 1.3 per 100,000 children under age 5 in the post-vaccine era has stabilized because disease from nonvaccine serotypes has replaced disease from vaccine serotypes.  This means that the risk of pneumococcal meningitis in a highly vaccinated population is due to the nonvaccine serotypes, and is the same risk for unvaccinated and vaccinated children.  Therefore, the cumulative incremental risk of permanent injury if not vaccinated until age 5 is zero.

 

References:

[1] Centers for Disease Control and Prevention: Epidemiology and Prevention of Vaccine-Preventable Disease. Atkinson W, Wolfe S, Hamborsky J, McIntyre L. eds. 11th edition. Washington D.C.: Public Health Foundation, 2009.

[2] Lochay et al. Association between Carriage of Streptococcus pneumoniae and Staphylococcus aureus in Children.  JAMA. 2004;292(6):716-720. doi: 10.1001/jama.292.6.716

[3] Yochay et al. Interference between Streptococcus pneumoniae and Staphylococcus aureus: In Vitro Hydrogen Peroxide-Mediated Killing by Streptococcus pneumoniae. Journal of Bacteriology, July 2006, p. 4996-5001, Vol. 188, No. 13. 0021-9193/06/$08.00+0 doi:10.1128/JB.00317-06
[4] Bogaert. Colonisation by Streptococcus pneumoniae and Staphylococcus aureus in healthy children. Lancet. 2004 Jun 5;363(9424):1871-2.

[5] Lysenko ES, Ratner AJ, Nelson AL, Weiser JN (2005) The Role of Innate Immune Responses in the Outcome of Interspecies Competition for Colonization of Mucosal Surfaces. PLoS Pathog 1(1): e1. doi:10.1371/journal.ppat.0010001

[6] Revai et al. Effect of Pneumococcal Conjugate Vaccine on Nasopharyngeal Bacterial Colonization During Acute Otitis Media. PEDIATRICS Vol. 117 No. 5 May 2006, pp. 1823-1829 (doi:10.1542/peds.2005-1983)

[7] Hicks LA, Harrison LH, Flannery B, Hadler JL, Schaffner W, Craig AS, Jackson D, Thomas A, Beall B, Lynfield R, Reingold A, Farley MM, Whitney CG. Incidence of pneumococcal disease due to non-pneumococcal conjugate vaccine (PCV7) serotypes in the United States during the era of widespread PCV7 vaccination, 1998-2004. J Infect Dis. 2007;196(9):1346-54.

[8] Hsu K, Pelton S, Karumuri S, Heisey-Grove D, Klein J; Massachusetts Department of Public Health Epidemiologists. Population-based surveillance for childhood invasive pneumococcal disease in the era of conjugate vaccine. Pediatr Infect Dis J. 2005;24(1):17-23.

[9] Hsu KK, Shea KM, Stevenson AE, Pelton SI; Massachusetts Department of Public Health. Changing serotypes causing childhood invasive pneumococcal disease: Massachusetts, 2001-2007. Pediatr Infect Dis J. 2010;29(4):289-93.

[10] Loughlin AM, Marchant CD, Lett SM. The Changing Epidemiology of Invasive Bacterial Infections in Massachusetts Children, 1984 through 1991. Am J Public Health. 1995 March; 85(3): 392-394.

[11] Techasaensiri, C et al. Epidemiology and Evolution of Invasive Pneumococcal Disease Caused by Multidrug Resistant Serotypes of 19A in the 8 Years After Implementation of Pneumococcal Conjugate Vaccine Immunization in Dallas, Texas. Pediatric Infectious Disease Journal: April 2010 – Volume 29 – Issue 4 – pp 294-300

[12] Jacobs, MR et al. Emergence of Streptococcus pneumoniae Serotypes 19A, 6C, and 22F and Serogroup 15 in Cleveland, Ohio, in Relation to Introduction of the Protein-Conjugated Pneumococcal Vaccine. Clin Infect Dis. (2008) 47 (11): 1388-1395. doi: 10.1086/592972

[13] Kornelisse RF, Westerbeek CM, Spoor AB, et al: Clin Infect Dis. 1995

Dec;21(6):1390-7

[14] Ostergaard C, Koradsen HB, Sauelsson S: BMC Infectious Diseases 2005, 5:93

[15] Ma JS, et al: J Microbiol Immunol Infect 2002;35(1):23-8

[16] Saha, SK et al.  Neurodevelopmental Sequelae in Pneumococcal Meningitis Cases in Bangladesh: A Comprehensive Follow-up Study. Clinical Infectious Diseases 2009; 48:S90-6