Monthly Archives: March 2016

Pneumococcal Vaccine (Pneumonia, Meningitis)

This is the LONG version. See also the SHORT version here.

streptococcus_pneumoniae_2

S. pneumoniae

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 was Weekly Topic 05, and pneumococcal will be discussed here.

There are two types of pneumococcal vaccines: conjugated (PCV) and unconjugated (PPSV). PPSV were the first created and are thus the oldest, but were generally recommended only in adults until very recently. PCV are newer and recommended primarily in children. According to the CDC Vaccination Schedule (2015), pneumococcal vaccination (primarily with PCV, followed by one PPSV dose) occurs at 2, 4, 6, and 12-18 months; if the series begins at 12 months, only two doses are recommended, and if it begins at 24 months, only one dose is recommended [1, 2]. In Canada, depending on province/territory, pneumococcal vaccination occurs typically at 2, 4, and 12 months, with a few recommending an additional 6 month dose and/or moving the 12 month dose to 18 months [3].

 

What is pneumococcus?

Streptococcus pneumoniae, often referred to as pneumococcus, is a bacterium and “one of the most extensively studied microorganisms” [4, p. 591]. It was first isolated in 1881 by Louis Pasteur himself. Some strains have capsules while others do not, but when simultaneously infected with both a capsular strain and a noncapsular strain, the noncapsular bacteria steal the capsular bacteria’s DNA and thereby create a capsule and convert to the same strain as the capsular bacteria. It’s also possible for capsular bacteria to steal other capsular bacteria’s DNA and begin making a new capsule. Since the capsule is how the serotype (strain) is determined, this is termed “serotype switching” or “capsular switching.” Capsular bacteria are 105 times more virulent than noncapsular strains. Based on unique characteristics of their capsules, the bacteria can be divided into over 90 serotypes. The serotypes vary drastically by geographic area; for example, in the 1980s, researchers found that the same 20 serotypes that are responsible for ~90% of infections in the U.S. and Europe were responsible for less than 70% of infections in Asia. Antibiotic resistance or sensitivity also varies significantly by geographic region, though they are generally sensitive to penicillins. [4, 5]

S. pneumoniae is commonly carried asymptomatically by healthy people, though the rates vary by population. For example, carriers may make up 20-60% of school-aged children, 5-10% of adults without children, and 50-60% of military personnel [5]. A study that tested several hundred children for pneumococci approximately every four weeks for two years found that 54% became carriers at least once by age 6 months and 97% became carriers at least once by age 2 years [6]. Carriage seems to be more common after influenza infection [4] and is more likely when the patient has recently had sinusitis, has one or more older siblings, is enrolled in daycare, or lives in the city [7]. One study of penicillin-resistant pneumococcus found asymptomatic carriage ranged from 3 days to 267 days (median 19 days) [8] and one study in mice found that lower number of bacteria was associated with longer carriage while a higher number of bacteria was quickly cleared [9]. Different serotypes are carried for different lengths of time and one study found that the duration of carriage ranged from 5.9 weeks (serotype 15C) to 19.9 weeks (serotype 6B), and that longer duration of asymptomatic carriage correlated to a lower incidence of disease [6]. Pneumococcal disease mostly occurs after new infection with a new serotype rather than after a long period of asymptomatic carriage [4]. Because carriage is so common, disease is relatively very rare.

The incubation period for pneumococcal infections is only 1-3 days and the symptoms include a sudden onset of fever and chills or rigors, as well as pleuritic chest pain; cough with rusty, mucousy sputum; shortness of breath; rapid breathing; low oxygen levels; rapid heart rate; malaise (general feeling of sickness); and weakness. Less commonly, patients also experience nausea, vomiting, and headaches [5]. It is the most common cause of pneumonia in adults; and is one of the most common causes of bacterial meningitis in children and adults, alongside the HiB and meningococcal bacteria discussed previously [4]. S. pneumoniae is also a common cause of otitis media (middle ear infections) [5].

Vaccines targeting S. pneumoniae were first developed in the early 1900s but were not effective and had many adverse effects. A more effective vaccine was developed in the 1930s, but the interest in antibiotics led to the vaccine being largely ignored, rarely used, and ultimately removed from the market. New pneumococcal vaccines were developed in the 1970s and 1980s. [4]

 

How can I prevent or treat pneumococcal infection in my child?

Conditions that make an individual more susceptible to pneumococcal disease include recent viral infection, immune suppression, and a generally unhealthy lifestyle [4]. Infection and carriage cannot be prevented (discussed later), so the best prevention of disease is to boost the immune system, avoid people who are sick, and engage in a generally healthy lifestyle.

The destruction of S. pneumoniae releases the toxin pneumolysin, which causes inflammation, and this toxin-mediated inflammation is thought to be responsible for the symptoms of pneumococcal disease. Furthermore, the bacteria also produce hydrogen peroxide, an oxidant which causes further damage and is thus also responsible for some of the symptoms of pneumococcal disease. This peumolysin- and hydrogen peroxide-mediated damage is thought to be responsible for enabling the bacteria to migrate into the lungs or bloodstream, causing pneumonia or invasive disease; the bacteria may migrate to the meninges and cause meningitis either through the bloodstream or directly through the nasopharynx (nose and throat). Furthermore, the pneumolysin damages the cilia in the host’s throat, making it more difficult to move mucus up and out, similarly to pertussis. Also similarly to pertussis, antibiotics attack the bacteria but do not repair the damage and thus may shorten the contagious period or prevent disease if given before symptoms develop but do not improve the progression of the disease or the outcome if given after symptoms have already developed. In fact, by killing the bacteria and thus releasing more of the bacteria’s pneumolysin toxin, antibiotics may actually worsen the disease. [4] Furthermore, unfortunately, the most common strains are also the strains most commonly antibiotic-resistant [7]. Addressing this inflammation and oxidation directly by the use of a safe anti-inflammatory and anti-oxidant that is also effective in the treatment of pertussis—such as vitamin C [10]—may help alleviate some of the symptoms and prevent progression to pneumonia and invasive disease.

 

How effective are the vaccines at preventing asymptomatic carriage?

“These three factors—increased carriage of vaccine-targeted strains, increased carriage of dangerous strains, and increased carriage of other bacteria—suggest ironically that vaccinated (not unvaccinated) children pose significant risk to the vulnerable members of the population and that vaccination therefore should not be relied upon for herd immunity.”

Pneumococcal carriage occurs among vaccinated individuals in proportions similar to unvaccinated individuals. For example, the CDC states, “Studies comparing patterns of pneumococcal carriage before and after PPSV23 vaccination have not shown clinically significant decreases in carrier rates among vaccinees” [5] and a study on PCV7 found that the overall rate of carriage did not change because the decrease in vaccine-targeted serotype carriage occurred alongside an increase in non-vaccine serotypes [11]. The same study found that there was no change in the distribution of asymptomatically carried PPSV23-targeted serotypes, in agreement with the CDC [11]. The CDC goes on to say that carriage of the vaccine-targeted strains may be reduced in recipients of the PCV [5], though it says nothing of serotype replacement (i.e., whether those serotypes are simply replaced by different serotypes, having no net effect on carriage rates). However, studies have demonstrated that extensive serotype replacement occurs with the PCV, with increased carriage occurring in the vaccinated. One study found carriage of nonvaccine serotypes to be 79% in vaccinated children vs. 42.5% in unvaccinated children; another found 39% in vaccinated vs. 21% in unvaccinated; and similar findings have been recorded in other studies [12]. Another study found the overall carriage rate did not change due to simultaneous increases in non-vaccine serotypes and decreases in vaccine-targeted serotypes [13].

The rate of carriage of vaccine-targeted strains is higher among those more recently vaccinated. For example, one study of asymptomatic carriage in children found that 73.1% of the isolates in children <2 years old, 68.9% of the isolates in children 2-5 years old, and 51.2% of the isolates in children >5 years old were vaccine-targeted strains. [7] This indicates that the vaccine increases the risk of asymptomatic carriage of the vaccine-targeted strains. This same study found that all of the invasive strains found in these asymptomatic carrier children were vaccine-targeted strains [7], indicating that vaccinated children may be more likely to be infected with a dangerous strain (because they are less likely to develop disease from it). Another study that compared carriage rates in the same communities before and after widespread use of the PCV7 found that the rate of carriage increased in those younger than 6 months (those most recently vaccinated) and decreased in those older than 36 months (those least recently vaccinated) [11]. Interestingly, this study also found that carriage of H. influenzae B (HiB) slightly and Moraxella catarrhalis significantly increased in the same timespan [11]. Another study duplicated those results, finding no change in S. pneumoniae carriage and increase in M. catarrhalis carriage. It also found that the vaccinated children were more likely to be carriers of pathogenic (disease-causing) bacteria [14]. Yet another study found that decreased pneumococcal carriage is associated with increased Staphylococcus aureus carriage, suggesting that pneumococcal vaccination may result in increased Staph infections [15].

These three factors—increased carriage of vaccine-targeted strains, increased carriage of dangerous strains, and increased carriage of other bacteria—suggest ironically that vaccinated (not unvaccinated) children pose significant risk to the vulnerable members of the population and that vaccination therefore should not be relied upon for herd immunity.

As discussed previously, pneumococcal asymptomatic carriage is more common after influenza infection. [4] I’m unaware of any studies on the effect of the live virus intranasal FluMist influenza vaccination on pneumococcal carriage in humans, but it’s reasonable to believe that FluMist recipients may be more susceptible to pneumococcal carriage than those who received an injected influenza vaccination or no influenza vaccination. This theory holds up to a study in mice, which found that live influenza vaccination increases carriage of S. pneumoniae and Staphylococcus aureus [16].

 

How effective is the pneumococcal vaccine?

The pneumococcal vaccines are said to protect against otitis media (ear infections), pneumonia, meningitis, and sepsis. If the infection moves past the ears and/or lungs to infect the normally sterile linings of the lungs (empyema), meninges of the brain (meningitis), or the blood (sepsis), it’s referred to as invasive pneumococcal disease (IPD). To explain the effectiveness of the pneumococcal vaccines, we’ll consider:

  1. Special Populations (in whom the vaccines may have varying efficacy),
  2. Serotype Replacement and Capsular Switching (which helps the bacteria avoid the pressures of the vaccine),
  3. Otitis Media, and
  4. Invasive Pneumococcal Disease, which will encompass
    • Pneumonia,
    • Meningitis, and
    • Sepsis

1. Special Populations

Unfortunately, the vaccine is not very effective at producing an antibody response in the populations that might benefit from it most: immune-suppressed patients (those lacking a spleen, infected with HIV, etc.), patients with frequent respiratory infections, the elderly, and young children [4]. Furthermore, after the introduction of the vaccine, there was an increase in drug-resistant IPD in the most susceptible populations (those aged <5 and 65+), and a decrease in drug-resistant IPD in the least susceptible populations (those aged 5-64) [17]. Another study in Alaska confirmed these findings, with an increase in the IPD rate in children under 2 and adults over 45, particularly in Alaska Natives, following PCV7 vaccination of infants and toddlers [13]. This poses particular danger to “the herd,” since the vaccine is associated with an increased incidence of disease in the populations most vulnerable to disease complications.

2. Serotype Replacement and Capsular Switching

It was thought that vaccination would be very effective because the majority of cases were caused by only a few serotypes [4], but some researchers warned that other serotypes may quickly move in to replace them (called “strain replacement” or “serotype replacement”) and that the new serotypes may be more dangerous [12]—in colloquial terms, it was a discussion of whether to fight “the devil you know or the devil you don’t.” They also warned that the pneumococci’s ability to switch its capsule in order to change serotype (“serotype switching” or “capsular-switching”) would mean that after infecting a host that had been vaccinated, the bacteria would simply change its serotype in order to avoid the host’s vaccine-induced defenses, a phenomenon called “vaccine escape” [12, 18] (as is the case with meningococcal bacteria [19]). Unfortunately, these researchers’ predictions were correct.

The CDC states that no change in serotypes was noted following the use of PPSV23 in adults [5]. However, serotype-replacement has been observed with the PCV, the first of which (PCV7) was licensed in 2000. For example, one 2004 CDC study examined only serotype 19A, a serotype not included in the PCV7, and found that it almost tripled in incidence between 1999 and 2004 (another study using the same data found that it more than quadrupled [17]), and that it had become more genetically diverse and more drug resistant. Furthermore, their results indicated that many clones (genetic bases) targeted by the vaccine took up the genetic code for the capsule of serotype 19A—in other words, the vaccine-targeted strains changed into serotype 19A, a strain not targeted by the vaccine, an example of capsular-switching as vaccine escape [18]; unfortunately, other studies have shown serotype 19A to be more dangerous, so the decrease in vaccine-targeted serotypes has nonetheless occurred alongside an increase in at least one more dangerous non-vaccine serotype [20]. Other studies have provided further evidence to support capsular-switching and oppose antibiotic-directed evolution as the causes of increases in non-vaccine serotypes [20, 21], though some studies have found that while drug-resistant bacterial samples decreased, drug-resistant infections caused by non-vaccine serotypes increased [13]. In most populations, serotype replacement occurs within 3-4 years after introduction of the vaccine [13].

[22] Note that this occurred in Salt Lake City, Utah, and may not be representative of the general population.

[22] Note that this occurred in Salt Lake City, Utah, and may not be representative of the general population.

The pre-licensure vaccine trials showed no changes in serotypes in response to vaccination. However, this was likely due to the fact that relatively few children were vaccinated in the trials, whereas post-licensure, the vast majority of children have received the vaccine. When the vaccine is used on a large scale, it pushes the serotypes to switch. [11, 12, 20] Populations where PCV7 use was widespread (such as Alaska Natives) experienced significant serotype replacement while populations where pneumococcal vaccination was low or moderate (such as Navajo and Australian aboriginal children) did not experience serotype replacement. In fact, the proportion of Alaska children receiving the pneumococcal vaccine was significantly higher than either the national average or any other individual state [13]. Ironically, this means the pneumococcal vaccine would be most effective in recipients if fewer children received it—the opposite of what is usually asserted.

Another potential issue is that some studies had incomplete data and so chose to extrapolate from the data they did have, essentially guessing about the data they didn’t have and using those guesses in their final results. For example, the 2004 CDC study mentioned above did not have the serotype data for all of the samples and so estimated the actual number and proportions of serotypes by extrapolating from the data they did have [17, 18]. It’s unclear how this affected the results.

Finally, and most likely to have the greatest effect on the results, many studies are of low methodological quality. A meta-analysis of studies on the effect of pneumococcal vaccination against pneumonia in older adults found that when only high-quality studies were included, the results were very homogenous: they all agreed that the vaccine is ineffective. However, when studies of all quality were included, the results were very heterogeneous: the effectiveness of the vaccine was uncertain. [23] In this regard, pneumococcal vaccine effectiveness studies mirror influenza vaccine effectiveness studies [24].

3. Otitis Media

“the vaccine slightly reduces the incidence of [ear infections] in some children, but increases the incidence of [ear infection] that is difficult to treat or comes back again and again”

At least 60% of acute otitis media (AOM) is viral, pneumococcus makes up about 25% of all AOM causes, and over 80% of children with AOM recover without antibiotics. The vaccine was not licensed for prevention of otitis media, though it was nevertheless widely advertised for that use since its introduction. It has been suggested that the vaccine was advertised for this purpose because ear infections are very common among vaccinated children while the more serious concerns of pneumonia and meningitis are very rare [25]. Although the drug manufacturer and others found the vaccine to result in a 6-7% reduction in AOM (there was approximately a 34% reduction in S. pneumoniae ear infections, but S. pneumoniae only caused 25% of ear infections pre-vaccine, so the total effect on ear infections was minimal) with simultaneous decreases in vaccine-targeted serotype AOM and increases in non-vaccine serotype AOM [14, 26, 27], it is not effective at reducing the incidence of recurrent ear infections [28]. Another study found that while pneumococcal ear infections decreased from 48% of ear infections to 31% of ear infections in pneumococcal-vaccinated children, other bacterial causes of ear infection doubled, more than replacing the drop in pneumococcal ear infections. Interestingly, one of the bacteria that increased was nontypeable H. influenzae [29] (for more information on HiB, please refer to our previous publication on that topic here). Other studies found increases in carriage of M. catarrhalis (which is more difficult to treat) and HiB, and that vaccinated children were more likely to be infected with pathogenic (disease-causing) bacteria, increasing the risk of antibiotic treatment failure and recurrent AOM [11, 14]. Another study found not only that there was no reduction in AOM among pneumococcal-vaccinated children, but also that pneumococcal-vaccinated children were more likely to have ear infections caused by Staphylococcus aureus, which poses serious concerns about antibiotic resistant ear infections caused by methicillin-resistant Staphylococcus aureus (MRSA) [15, 30]. Another study found no decrease in AOM in children who received pneumococcal vaccines compared to children who received hepatitis A or B vaccines [31], which may be an odd choice for comparison, given that the hepatitis A vaccine may cause AOM [32]; this means they compared the AOM rate after pneumococcal vaccines to the AOM rate after another vaccine which can cause AOM; as there was no difference in AOM rate between the PCV-vaccinated and Hep A-vaccinated children, this seems to indicate that PCV increases AOM rates. At any rate, that last odd study aside, the vaccine slightly reduces the incidence of AOM in some children, but increases the incidence of AOM that is difficult to treat or comes back again and again.

4. Invasive Pneumococcal Disease (IPD)

It’s difficult to say what impact the vaccine has on IPD because studies examining all serotypes have observed both a decrease [22] and an increase [21] in IPD. A study in Spain found the proportion of IPD cases caused by non-vaccine serotypes increased from 38% in the prevaccine period to 72% in the

[21]

[21]

postvaccine period with an increase in the total number of IPD cases [21]. Although about half of the children in the Spain study had received the PCV7, and this is suggested as a possible reason for the increase, the same phenomenon of sharply increased IPD (specifically due to non-vaccine serotype increases significantly outweighing the vaccine-targeted serotype decreases) was observed in Alaska as well, where the vast majority of the children had received the PCV7 (the proportion who had received at least 3 doses of PCV7 ranged from 88% in 2003 to 96% in 2006). Particularly interesting is that the proportion of IPD cases designated serious and requiring hospitalization also increased (i.e., IPD cases increased in number and became proportionately more dangerous) [13]. However, another 2004 study that looked at all serotypes found a simultaneous decrease in vaccine-targeted serogroups and increase in non-vaccine serogroups such that the total number of IPD cases did not change, though the proportion of cases caused by drug-resistant bacteria and the proportion of cases identified as serious or life-threatening increased. Especially important to note was that the cases caused by non-vaccine serotypes were the most severe [22], suggesting that the vaccine-targeted serotypes were replaced with more dangerous serotypes, which, as discussed above, researchers had previously warned might occur. It is interesting to note that the increase in drug resistance was noted in PCV7-targeted serotypes in one study [22] but in non-vaccine serotypes in another study [11], while another study found a decrease in drug resistance [21]. Another study found a decrease in drug-resistant bacteria overall but a total increase in drug-resistant IPD in young children and the elderly; and an increase in drug-resistant IPD caused by vaccine-targeted serotypes with the greatest increase in drug resistance in serotype 19A (the nonvaccine serotype which increased the most in overall number and proportion of cases) [17]. Other more recent studies have found further increases in both 19A and other non-vaccine serotypes as well as a further increase in drug-resistant pneumococcal infections among the vaccinated but not among the unvaccinated, with the risk highest among those who’d received the most doses of vaccine [20].

Why are the results so variable between studies? It’s probably mostly an issue of which populations are included in the study. For example, the CDC study mentioned above, which found a drop in total IPD cases and apparently no change in the seriousness of IPD cases [17, 18], did not include the population reported by another study, where there was no change in total IPD cases and an increase in serious and life-threatening cases [22]. As discussed previously, the proportions of each serotype vary significantly from population to population, so the vaccine may be very effective in one population and very ineffective in another. If a study of the entire nation, which necessarily must sample various populations rather than including every single case across the country, selectively studies the populations where the vaccine is most effective, as the CDC apparently did (probably unintentionally, since they examined data from the designated CDC surveillance sites), this will skew the results. For this reason, I’m afraid all that can really be said is some studies found the vaccine to be productive and others found the vaccine to be counter-productive, and unfortunately we can’t really know which is true for the general population, nor can we accurately predict which populations will be most benefitted by the vaccine or most harmed by it. (And I know that statement will be unpopular with both pro-vaxxers and anti-vaxxers. Sorry, not sorry.)

A. Pneumonia

“…in children, the vaccine may increase or slightly reduce the incidence of pneumonia but increases the incidence of severe pneumonia that is more dangerous and more difficult to treat. [….] …pneumococcal vaccination does not prevent pneumonia in older adults… but was associated with an increase in severe pneumonia requiring hospitalization.”

In 2004, just four years after the PCV7 was licensed, researchers noted an increase in parapneumonic empyema (a very severe form of pneumonia where the lining of the lungs becomes infected, with mortality as high as 30% in non-immunocompromised patients) caused by pneumococci in spite of decreases in pneumococcal disease and pneumococcal pneumonia, data which confirmed previous studies [22]. A Cochrane Review from 2004 found no effect of PCV7 on clinical pneumonia rate [33] while the Cochrane Review from 2009 found that PCV7 slightly decreases the clinical pneumonia rate [34]. However, a more recent study from 2010 found that PCV7 vaccination was associated with an increase in drug-resistant pneumonia among the PCV7-vaccinated but not among the PCV7-unvaccinated [20]. As discussed above, serotype prevalence differs significantly from population to population and so the vaccine may be very effective in one population and very counter-productive in another. This was exemplified in Britain, where the PCV7 was introduced in 2006, and by 2008, health authorities noted that the incidence of empyema (very severe pneumonia) had risen significantly, due in part to the 10-fold rise in serotype 1 (not included in the vaccine). Though the rise in serotype 1 began before introduction of the vaccine and thus cannot be blamed solely on the vaccine, serotype-replacement surely contributed [35]. Spain also saw an overall increase in IPD in children under 2 after introduction of the PCV7, including a more than fourfold increase in pneumonia [21]. Alaska saw the same pattern, with an overall increase in pneumonia cases and an increase in the proportion of pneumonia cases that involved empyema [13]. In other words, in children, the vaccine may increase or slightly reduce the incidence of pneumonia but increases the incidence of severe pneumonia that is more dangerous and more difficult to treat.

A rigorous meta-analysis published in 2009 found that pneumococcal vaccination does not prevent pneumonia in older adults [23]. As in studies of children discussed above, the use of the PPSV in elderly adults was not associated with a decrease in pneumonia, but was associated with an increase in severe pneumonia requiring hospitalization [36].

B. Meningitis

A study in Spain found that though the rates of sepsis and pneumonia increased after introduction of the PCV7, the rate of meningitis decreased. Nevertheless, the decrease in meningitis cases was not great enough to offset the large increases in pneumonia and sepsis [21].

C. Sepsis

Also called septicemia or bacteremia and “blood poisoning,” this refers to a bacterial infection of the blood. A study in elderly adults found a decrease in pneumococcal sepsis following pneumococcal vaccination, but did not examine other potential causes of sepsis [36]. However, as early as 2004, researchers noted that the number of invasive pneumococcal disease cases did not change due to simultaneous decreases in vaccine-targeted serogroups and increases in non-vaccine serogroups, and there was an increase in cases of severe disease (those classified as “serious” or “life-threatening”) [22]. In 2005, researchers noted that though the overall pneumococcal IPD rate decreased, the proportion of IPD cases caused by non-vaccine serogroups increased (a form of serotype replacement), and the proportion of cases caused by drug-resistant bacteria increased [18]. Studies in other countries, such as Spain, confirmed some of these results. Oddly, the Spain study found that sepsis rates overall increased (from a per 100,000 population rate of 14.5 to 21.4 in children <2 and 1.5 to 5.8 in children 2-4) and the specific causes of sepsis that increased in incidence were S. pneumoniae, the species targeted by the vaccine, and E. coli [21]. A study in Alaska also found an increase in bacteremia [13].

 

So if it’s not effective, why did it get licensed and put on the CDC vaccine schedule?

Of the 12 committee members at the FDA responsible for determining whether to approve Prevnar for licensing, four had financial ties to the drug company making Prevnar. Of those four, three were granted waivers so that they could still vote. [37] For this reason, some believe the committee’s approval of the pneumococcal vaccine was largely a matter of bias. For a long time, Prevnar was the most expensive vaccine on the market. At one time, Prevnar alone accounted for 40% of the cost of vaccination according to the CDC schedule. Financially speaking, Prevnar performed exceptionally well compared to other vaccines.

 

Are there other infectious diseases related to pneumococcal 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. [38] 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. [39, 40]

 

What are the risks of the vaccine?

Prevnar has a troubled history. As mentioned above, there were significant financial conflicts of interest in the licensing process. Furthermore, a whistleblower came forward in 2004 with allegations that the company was violating certain FDA rules regarding quality control [41]. Many in developing nations such as Argentina were apparently coerced into participating in the Prevnar vaccine trials under threat of having their children taken from them if they refused [42]. It was also halted or outright banned in many countries shortly after introduction due to severe adverse reactions, particularly death, including, but not limited to, the Netherlands [43], Portugal [44, 45], Japan [46], and India [47].

The drug company making Prevnar performed short-term safety studies in which Prevnar was compared to an experimental vaccine. Prevnar was found to cause more seizures and rashes, and higher fevers than the experimental vaccine. Prevnar was not compared to a placebo. [25, 37]

Please note that having had the vaccine once without any serious reactions does not mean serious reactions will not happen with future vaccination. For example, this article reported a case where a patient with previous pneumococcal vaccination nevertheless had a serious local reaction (severe pain and swelling that extended beyond the area of the injection) upon repeat vaccination [48] and, in fact, reactions are more common in those who have had the vaccine before than in those receiving the vaccine for the first time [49].

Seizures. One study conducted by the vaccine manufacturer found seizures to occur four times as often in children receiving the pneumococcal vaccine than in children receiving another experimental vaccine (it was not compared to a saline placebo) [25].

Asthma. One study found the incidence of asthma in pneumococcal-vaccinated children (2.96/1000) was nearly double the incidence in pneumococcal-unvaccinated children (1.66/1000). The authors postulated that this was related to “the hygiene hypothesis of decreased childhood infections” [50]. The hygiene hypothesis notes that children who have fewer childhood infections (including measles and hepatitis A) have a higher incidence of allergies and asthma, and hypothesizes that induction of a Th1 response early in life prevents or even reverses the imbalanced Th1/Th2 ratio in people who are prone to asthma [51].

Thrombocytopenia. The vaccine has been noted to cause relapses of immune thrombocytopenia [52].

Autoimmune Diseases. Pneumococcal vaccination has been shown to cause onset or rebound of the following autoimmune conditions: idiopathic thrombycytopenic purpura, peripheral and central demyelinating disease, Henoch-Schönlein Purpura (a form of leukocytoclastic vasculitis), Guillain-Barre Syndrome, minimal-change nephritic syndrome, neuromyelitis optica (a.k.a., optic neuritis), Sweet’s syndrome, autoimmune hemolytic anemia, systemic lupus erythematosus, migrating arthralgia, angioimmunoblastic lymphadenopathy with dysproteinemia (a type of lymphoma), and chronic fatigue syndrome. It has been involved in at least two cases of bullous phemigoid, myositis, but other vaccines were given simultaneously, so causation with pneumococcal vaccination cannot be demonstrated. These conditions have largely occurred following PPV rather than PCV, as the PCV is too new for most autoimmune conditions to have presented themselves and is given primarily in children, in whom many autoimmune reactions are missed due to age-related difficulty expressing or recognizing symptoms [53]

Local Reactions. Local reactions, such as severe pain and swelling that extends far beyond the area of the injection, have been reported to occur even in those who have previously received pneumococcal vaccination or had extensive laboratory contact with pneumococci with no previous reaction [48]. These local reactions may mimic cellulitis and have high white blood cell counts, leading to unnecessary hospitalization and antibiotic treatment if the treating physician is unaware that this is a typical, noninfectious reaction to the vaccine. A local reaction occurs in as many as 50% of vaccine recipients, with the highest rate in those who have previously had pneumococcal vaccination [49].

Apnea in Preemies. Apnea (temporary suspension of breathing) has been observed in premature infants who receive Prevnar. [54]

Bronchiolitis, Gastroenteritis, Pneumonia. Ironically, one of the most common serious adverse events following this pneumonia vaccine is pneumonia. [54]

Hypotonic-Hyporesponsive Episodes. This is similar to fainting; the child may be awake but have altered consciousness. This is one of the most common serious adverse reactions reported. [54]

 

What vaccines are offered against pneumococcal?

In the U.S., there are two pneumococcal vaccines, the PCV13 (the replacement for PCV7), which targets 13 strains and is recommended for children under 5 and adults over 64 (and those aged 6+ who are at high risk), and the PPSV23, which targets 23 strains and is recommended for adults over 64 (and those aged 2-64 who are at high risk). (NOTE: These ingredients lists are not complete; they only list the most alarming ingredients.)

  • Prevnar 13: diphtheria-pneumococcal (diphtheria CRM197 protein, pneumococcal 13 serotypes, soy, yeast, ammonium sulfate, polysorbate 80, aluminum) [54]
  • Pneumovax 23: pneumococcal (pneumococcal 23 serotypes, phenol) [55]

 

So what’s the bottom line?

The bottom line is that S. pneumoniae is so common that almost 100% of the population carries it at some point and develops some degree of immunity by age 2. There are over 90 serotypes, and the bacteria easily change their serotype (serotype switching) to avoid the host’s vaccine-induced defenses. The vaccine does not prevent asymptomatic carriage—in fact, it may increase asymptomatic carriage not only of S. pneumoniae but also of other bacteria—and so cannot contribute to herd immunity and may, in fact, pose greater risk to the herd. The vaccine is said to protect against ear infections, pneumonia, meningitis, and sepsis, but may actually be ineffective for all of these purposes due partly to serotype switching and serotype replacement, and partly to increases in other bacteria. The serotypes not covered by the vaccines are more dangerous, and so the proportion of serious infections is higher in vaccinated children than in unvaccinated children. Because it is mostly ineffective, the risks, no matter how mild, outweigh the benefit.

 

References

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

[2] http://www.cdc.gov/vaccines/vpd-vac/pneumo/default.htm

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

[4] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC239389/pdf/590591.pdf

[5] http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/pneumo.pdf

[6] http://jid.oxfordjournals.org/content/194/5/682.full

[7] http://wwwnc.cdc.gov/eid/article/8/5/01-0235_article

[8] http://www.ncbi.nlm.nih.gov/pubmed/9402367

[9] http://www.ncbi.nlm.nih.gov/pubmed/24749506

[10] http://www.vaccinationcouncil.org/2012/09/07/vitamin-c-for-whooping-cough-updated-edition-suzanne-humphries-md/

[11] http://pediatrics.aappublications.org/content/116/3/e408.full-text.pdf

[12] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2640786/pdf/10341170.pdf

[13] http://jama.jamanetwork.com/article.aspx?articleid=206757

[14] http://www.ncbi.nlm.nih.gov/pubmed/16651345

[15] http://jama.jamanetwork.com/article.aspx?articleid=199212

[16] http://mbio.asm.org/content/5/1/e01040-13.full

[17] http://www.nejm.org/doi/full/10.1056/NEJMoa051642

[18] http://jid.oxfordjournals.org/content/192/11/1988.long

[19] See the previous Meningococcal Weekly Topic located here: https://schaabling.wordpress.com/2016/01/01/meningococcal-vaccine-meningitis/

[20] http://jama.jamanetwork.com/article.aspx?articleid=186547

[21] http://cid.oxfordjournals.org/content/46/2/174.long

[22] http://cid.oxfordjournals.org/content/41/1/21.full.pdf+html

[23] http://www.cmaj.ca/content/180/1/48.full

[24] Per Cochrane Collaboration: “An earlier review of 274 influenza vaccine studies in all age groups (including most of the studies in this review) showed an inverse relationship between risk of bias and the direction of study conclusions. Conclusions favourable to the use of influenza vaccines were associated with a higher risk of bias. In these studies, the authors made claims and drew conclusions that were unsupported by the data they presented. In addition, industry-funded studies are more likely to have favourable conclusions, to be published in significantly higher-impact factor journals and to have higher citation rates than non-industry-funded studies. This difference is not explained by either their size or methodological quality (Jefferson 2009a). Any interpretation of the body of evidence in this review should be made with these findings in mind.” http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD001269.pub5/full

[25] https://web.archive.org/web/20010605115354/http://www.wfaa.com/wfaa/articledisplay/0,1002,20489,00.html

[26] http://www.nejm.org/doi/full/10.1056/NEJM200102083440602#t=article

[27] http://cid.oxfordjournals.org/content/40/12/1738.long

[28] http://www.ncbi.nlm.nih.gov/pubmed/16510637

[29] http://www.ncbi.nlm.nih.gov/pubmed/15361721

[30] http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(03)13772-5/fulltext

[31] http://www.thelancet.com/journals/lancet/article/PIIS0140673603137725/abstract

[32] http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM110049.pdf

[33] http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD004977/abstract NOTE: The link provided goes to the abstract; however, the information about clinical pneumonia is in the full text of the article, not in the abstract.

[34] http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD004977.pub2/abstract

[35] http://www.independent.co.uk/life-style/health-and-families/health-news/increase-in-severe-pneumonia-in-children-may-be-caused-by-vaccine-808633.html

[36] http://columbiamedicine.org/education/r/ID/Outpatient%20and%20Prevention/Pneumonia%20Vaccine.pdf

[37] https://web.archive.org/web/20010825174745/http://www.wfaa.com/wfaa/articledisplay/0,1002,20550,00.html

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

[39] “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.

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

[41] https://www.lawyersandsettlements.com/articles/whistleblower/wyeth-00187.html

[42] http://abcnews.go.com/Health/story?id=5735276&page=1

[43] http://www.dutchnews.nl/news/archives/2009/11/vaccine_use_halted_after_baby

[44] https://web.archive.org/web/20120531095007/http://www.oserledire.com/article-portugal-suspension-des-vaccins-prevenar-et-rotateq-apres-effets-secondaires-graves-102046008.html

[45] http://www.rtp.pt/noticias/mundo/infarmed-suspendeu-vacinas-rotateq-e-prevenar-13-por-suspeita-de-reacao-adversa_n537610

[46] http://blogs.wsj.com/health/2011/03/07/scrutinized-in-japan-pfizers-prevnar-vaccine-is-used-widely-in-u-s/

[47] http://www.livemint.com/Home-Page/j4W7C2aW2imlLjKZPUSfNM/Wyeth-drug-tests-fall-foul-of-watchdog.html

[48] http://www.ncbi.nlm.nih.gov/pubmed/7355337

[49] http://www.tandfonline.com/doi/full/10.4161/hv.28559

[50] http://www.nejm.org/doi/full/10.1056/NEJMoa035060#t=article

[51] http://www.tandfonline.com/doi/abs/10.3109/07853890008995946

[52] http://jama.jamanetwork.com/article.aspx?articleid=377409

[53] Shoenfeld, Y., Agmon-Levin, N., & Tomljenovic, L. (2015). Vaccines and Autoimmunity (pp. 193-195, 227, 323, 340, 346, 354). Hoboke, NJ: Wiley Blackwell.

[54] http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM201669.pdf

[55] http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM257088.pdf

Pneumococcal Vaccine (Pneumonia, Meningitis) SHORT

This is the short version. See the long version with references here.

streptococcus_pneumoniae_2

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 (Weekly Topic 05), pneumococcal, and meningococcal (Weekly Topic 03).

There are two types of pneumococcal vaccines: conjugated (PCV) and unconjugated (PPSV).

What is pneumococcus?

Streptococcus pneumoniae, often referred to as pneumococcus, is a bacterium. It may have a capsule or not have a capsule. The structures on the capsule determine its serotype. It can adopt or change its capsule, thus changing its serotype. This is called “serotype switching.” There are over 90 serotypes. Which serotypes are most common and how many are resistant to drugs varies significantly by geographic location.

S. pneumoniae is normally carried by healthy people with no symptoms (asymptomatic carriers). Depending on the population, 5-60% may be carriers. About half of babies become carriers by age 6 months and almost 100% become carriers by age 2 years. Carriage is more common after viral infection (especially influenza). Asymptomatic carriage typically lasts months. Because carriage is so common, disease is relatively rare.

S. pneumoniae is a common cause of otitis media (middle ear infection). If disease develops, complications are uncommon but include pneumonia, meningitis, and sepsis.

How can I prevent or treat pneumococcal infection in my child?

Conditions that make an individual more susceptible to pneumococcal disease include recent viral infection, immune suppression, and a generally unhealthy lifestyle. The best prevention is to boost the immune system, avoid people who are sick, and engage in a generally healthy lifestyle. The vitamin C protocol for pertussis may help treat pneumococcal infection.

How effective are the vaccines at preventing asymptomatic carriage?

Neither PPSV nor PCV decrease asymptomatic carriage. Some studies find that asymptomatic carriage increases with PCV. After PCV, vaccine-targeted pneumococcal serotypes decrease but non-vaccine serotypes increase (called “serotype replacement”), and carriage of other species of bacteria (including HiB, M. catarrhalis, and Staphylococcus aureus) increase. FluMist vaccination also increases carriage of S. pneumoniae and Staph.

How effective is the pneumococcal vaccine?

The pneumococcal vaccines are said to protect against otitis media (ear infections), pneumonia, meningitis, and sepsis. If the infection moves past the ears and/or lungs to infect the normally sterile linings of the lungs (empyema), meninges of the brain (meningitis), or the blood (sepsis), it’s referred to as invasive pneumococcal disease.

1. Special Populations. The vaccine is less effective in the populations who are most susceptible to complications from pneumococcus: immunosuppressed patients, patients with frequent respiratory infections, the elderly, and young children. Some studies found that vaccination of children with PCV was followed by an increase in drug-resistant pneumococcal infections in young children and/or the elderly.

2. Serotype Replacement. S. pneumoniae can change its serotype after infecting someone. When one serotype is targeted by a vaccine, the bacteria can simply infect the vaccinated child and then switch its serotype in order to bypass the child’s defenses. This is called “vaccine escape.” The newest PCV targets 13 serotypes, but there are over 90 pneumococcal serotypes. After vaccination, researchers noted significant serotype replacement, which has often resulted in no change or an increase in the total number of IPD cases. Some studies have also shown an increase in antibiotic resistance.

3. Otitis Media (Ear Infection). At least 60% of acute otitis media (AOM) is viral, pneumococcus makes up about 25% of all AOM causes, and over 80% of children with AOM recover without antibiotics. Studies have found either a 6-7% decrease or no change in AOM; no change in recurrent AOM; and an increase in other serotypes (serotype replacement) and other species of bacteria which are more likely to be antibiotic resistant and harder to treat. In other words, the vaccine may or may not affect the rate of AOM but increases the likelihood that AOM will be difficult to treat.

4. Invasive Pneumococcal Disease (IPD). Studies vary significantly, with results ranging from a decrease to no change to an increase in IPD; however, serotype replacement is common. Disease caused by non-vaccine serotypes is more severe and some studies report it is also more likely to be antibiotic-resistant and more difficult to treat. The worst effects occur in the very young, the very old, and those who’ve received the most doses of the vaccine.

a. Pneumonia. In children, studies find slight decrease, no change, or significant increase in overall pneumonia cases; extensive serotype replacement; and an increase in empyema (severe pneumonia). In other words, the vaccine may or may not affect the rate of pneumonia in children, but it increases the rate of severe pneumonia that is difficult to treat. In older adults, pneumococcal vaccination is ineffective.

b. Meningitis. Studies seem to agree that meningitis rates decrease, but this drop in meningitis occurs alongside an increase in pneumonia and sepsis.

c. Sepsis. Studies have found decrease, increase, or no change in sepsis rate; extensive serotype replacement; and increases in severe disease, drug-resistant cases, and cases caused by other bacteria (notably E. coli). In other words, the vaccine may or may not affect the sepsis rate, but makes it more difficult to treat.

What are the risks of the vaccine?

A short list of the most concerning risks includes:
• seizures
• asthma
• thrombocytopenia
• autoimmune diseases
• local reactions that will be mistaken for infection and result in unnecessary hospitalization and antibiotic use

So what’s the bottom line?

S. pneumoniae is so common that almost 100% of the population carries it and develops some degree of immunity by age 2. There are over 90 serotypes, and the bacteria easily change their serotype to avoid the host’s vaccine-induced defenses. The vaccine may increase asymptomatic carriage not only of S. pneumoniae but also of other bacteria and so cannot contribute to herd immunity and may actually pose greater risk to the herd. The vaccine is said to protect against ear infections, pneumonia, meningitis, and sepsis, but may actually be ineffective for all of these purposes due partly to serotype switching and serotype replacement, and partly to increases in other bacteria. The serotypes not covered by the vaccines are more dangerous, and so the proportion of serious infections is higher in vaccinated children than in unvaccinated children. Because it is mostly ineffective, the risks, no matter how mild, outweigh the benefit.