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The Childhood Vaccination Schedule – Part 4: The Hib Vaccine

By April 15, 2024April 17th, 2024No Comments

So far, we have taken an in-depth look at three of the vaccines currently on the childhood vaccination schedule in the United States—the HepB vaccine, the Rotavirus vaccine, and the DTaP vaccine.

In this installment of our 14-part series we will examine the Hib vaccine.

First, let’s set the stage with a few facts about childhood vaccines in the US.

In the first six months of life, infants in the US may receive as many as 20 doses of 14 or more different vaccines.  

Children whose parents follow the entire Child and Adolescent Immunization Schedule recommended by the US Centers for Disease Control and Prevention (CDC) have been given more than 50 injections of 90 antigens between the day of birth and 18 years of age. (Some shots, such as DTaP, have multiple components.)

With the recent addition of respiratory syncytial virus (RSV) and SARS-CoV-2 (Covid-19) shots to its ever-increasing vaccination schedule, the CDC is advising that children be inoculated for 18 different diseases by the time they turn 18.  

From the mid-1980s to today, the agency’s recommended doses of childhood vaccines have more than quadrupled.

Compared to other countries, the US’ CDC schedule is the most aggressive in the world.

The Hib vaccine is a relatively recent addition to the schedule. Manufacturers of the five current Hib vaccines market them as a way to provide immunity against Haemophilus influenzae type b, a bacterium that allegedly causes severe infections in infants and young children. 

This article will recount the details of how the Hib vaccine came into existence and then discuss the problems that have arisen from the five Hib vaccines presently on the childhood schedule.

In 1892, Richard Pfeiffer proposed a causal association between a certain bacterium and the respiratory infection known as influenza (the flu).

In 1917, the genus of the bacterium was given the name Haemophilus by Charles-Edward Winslow et al.

In 1933, the medical and scientific establishment deemed influenza to be caused by an alleged virus and proposed the theory that H. influenzae, in particular, led to secondary infections.

However, two years earlier, in 1931, Margaret Pittman, PhD, from the Hospital of The Rockefeller Institute for Medical Research had already established, in an article titled “Variation and Type Specificity in the Bacterial Species Hemophilus Influenzae,” that Haemophilus was part of the normal bacterial flora in the upper respiratory tract and was not the cause of influenza.

Nonetheless, the name “influenza” stuck and remains a testimony to misconceptions of the past.

The first Hib vaccine

In 1985, the first Hib vaccine, a pure polysaccharide vaccine, was licensed for use in the United States. It was proven to have low effectiveness. 

As a 1988 study in Pediatrics explained:

[I]t was known that the vaccine induced essentially no antibody response or protection in children less than 18 months old.   

A study from Minnesota that same year concluded the Hib vaccine had a negative protection rate:

The vaccine’s protective efficacy for children who were most likely to be protected by vaccination was -55% (95% confidence interval = -238% to 29%). Our results indicate that vaccination with Haemophilus b polysaccharide vaccine had no effect in preventing H influenzae type b disease in Minnesota children.

Additional studies cited an increased risk of Hib disease within seven days of receiving the Hib vaccine.

For example, another 1988 study in Pediatrics, “Haemophilus influenza Type b Vaccines: Lessons for the Future,” intimated that the initial polysaccharide Hib vaccine may have been rushed to market. It concluded:

“We believe many important lessons can be gained from the experience with the first-generation vaccine. In the case of the H influenza type b polysaccharide vaccine controversy, there has been almost too much evidence, so that the task has been to determine what is real, what is important, and what is artifact. The issues we reviewed regarding the case-control studies of H influenza type b polysaccharide vaccine should be relevant to future studies with the H influenza type b conjugate vaccines and other vaccines as well. We hope that unrealistic expectations and misunderstanding can be avoided in the future recommendations for use of new vaccines.”

The next year, 1989, the Hib pure polysaccharide vaccines were discontinued and replaced by conjugated forms of the vaccine. Conjugated vaccines combine a weak antigen with a strong antigen as a carrier under the premise that the immune system will have a stronger response to the weak antigen when it is connected to a strong antigen.

The first conjugated Hib vaccine in the US, ProHIBIT, linked the Haemophilus b capsular polysaccharide to a diphtheria toxoid. It was licensed in 1987

In 1988, the CDC’s Advisory Committee on Immunization Practices (ACIP) recommended that all children receive the conjugate vaccine at 18 months of age or older—even while noting that “the efficacy of conjugate vaccine in children 18 months of age or older has not been determined in field trials.” 

In less-than-convincing fashion ACIP added:

[S]tudies comparing antibody production in children receiving conjugate vaccine with that in children receiving polysaccha­ride vaccine suggest that conjugate vaccine is likely to be more effective than the polysaccharide vaccine”, with the further admission, “While the duration of immunity after a single dose of conjugate vaccine is unknown at this time, it is expected to be at least 1.5 to 3 years. [Emphasis added.]

These “best guesses” were based on comparative studies with the already-proven-to-be-ineffective Hib polysaccharide vaccine, yet they were deemed sufficient by ACIP to recommend use.

The rush to develop conjugate Hib vaccines was on.

Between 1988 and 1994, manufacturers introduced various types of conjugate vaccines, using different protein carriers. Their efforts were in conjunction with CDC/ACIP recommendations for expanded use of Hib vaccines.

The Hib Parade

The second Hib conjugate vaccine, HibTITER, a product of Lederle-Praxis Biologicals, was licensed by the US Food and Drug Administration (FDA) in December 1988 for children 18 months and over. In April of 1990 ACIP issued a recommendation for routine use of the Hib vaccine beginning at 15 months of age.

In October of 1990 the FDA approved Lederle-Praxis’ Haemophilus B vaccine to be administered as part of the routine three-dose primary vaccine series for infants at ages two, four and six months. This came six weeks after the FDA’s Vaccine and Related Biological Products Advisory Committee (VRBPAC) determined that the vaccine was safe for infants under 15 months of age. These new guidelines also called for booster shots at 15 months or older.

These updated regulatory endorsements gave Lederle-Praxis “a victory in the three-way race in the U.S. to become the first producer of a Haemophilus B conjugate vaccine approved for use in small infants.”

But prior to the December 1988 approval of HibTITER as well as post-approval, Praxis was found to have engaged in misleading promotional activities. (Praxis was bought by Lederle Labs in June of 1989.) The FDA concluded:

Praxis engaged in a series of events designed to promote and commercialize the product HibTITER as safe and effective for purposes for which it was being investigated.

It was documented that Praxis distributed professional materials and placed an ad in Contemporary Pediatrics claiming that its vaccine was “a more effective vaccine than a competitive vaccine because it elicits a stronger immunogenic response”—a claim “not supported by data available to FDA.”

The FDA also asserted that, even after the vaccine was approved, “Praxis was in violation of the Federal Drug and Cosmetic Act on at least five occasions.” For example:

“In a letter to physicians in February 1989, Praxis called HibTITER ‘the most advanced conjugated vaccine,’ noting that the product’s ‘lack of “chemical linkers”‘ reduces the number of allergic reactions. FDA said that “there is no evidence’ to support such a claim.

“Around the same time [. . .] Praxis salespeople were suggesting in ‘written materials and oral statements’ that the conjugate vaccine could be used in infants. ‘The representation and suggestion that HibTITER could be used, and would provide protection, in infants under the age of 18 months was not an approved indication and the labeling did not contain adequate directions for use,’ FDA maintained.”

Even though the FDA considered these practices by Praxis to be deceptive, the agency ultimately licensed the vaccine for infants.

Lederle defended itself by saying that, while it did own Praxis at the time of the deceptive promotions, most of the violations occurred prior to the Lederle and Praxis merger, when the marketing and sales organizations were not yet fully integrated. 

Lederle reassured regulators and the public that “Praxis sales and marketing groups have been disbanded and now the sales of HibTITER are through the Lederle Laboratories’ ethical sales force.” 

In 1989, PedvaxHIB, a conjugated Hib vaccine bound to a meningococcal protein manufactured by Merck Sharp & Dohme Corp. (MSD), received FDA approval for use in children 18 months of age and older.

In 1990, the FDA expanded the use of PedvaxHIB to include infants two months and up.

In 1993, two more conjugated Hib vaccines were approved for use in infants—Sanofi Pasteur Ltd.’s ActHIB, a polyribosyl-ribitol phosphate-tetanus toxoid conjugate Haemophilus b vaccine (PRP-T), and Tetramune, a combined diphtheria and tetanus toxoid and whole cell pertussis vaccine (DTP) and Haemophilus b conjugate vaccine made by Lederle-Praxis.

In September 1993, ACIP issued recommendations for the use of both the available Haemophilusb conjugate vaccines and the combined diphtheria, tetanus, whole cell pertussis, Haemophilusb conjugate vaccine. 

In 1996, the first combined diphtheria, tetanus, acellular pertussis, and Haemophilusb vaccine, TriHIBit, received FDA approval. TriHIBit combined Tripedia, a diphtheria and tetanus toxoid and acellular pertussis vaccine, with the Hib conjugated vaccine, ActHIB. TriHIBit and Tripedia were discontinued in 2011.

In 2008, Pentacel, a 5-in-1 multivalent antigen, combining the 3-in-1 diphtheria toxoid and tetanus toxoid and acellular pertussis (DTaP) vaccine, the inactivated poliovirus (IPV) vaccine, and the Hib vaccine, was manufactured by Sanofi Pasteur, Ltd. It was approved for use as a four-dose series at 2, 4, 6, and 12 months. Pentacel contained twice as much detoxified pertussis toxin (PT) and four times as much filamentous hemagglutinin (FHA) as Sanofi Pasteur’s DAPTACEL vaccine.

In 2009, in response to a shortage of available Hib vaccines, the FDA fast-tracked GlaxoSmithKline’s (GSK) HIBERIX under the Accelerated Approval Regulations (AAP): 

[The AAP program allows for] “earlier approval of drugs that treat serious conditions, and fill an unmet medical need based on a surrogate endpoint. A surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign, or other measure that is thought to predict clinical benefit but is not itself a measure of clinical benefit.”[Emphasis added.]

Once GSK expedited the approval process by using this surrogate endpoint, HIBERIX was approved for use in children between the ages of 15 months and four years of age.

In 2016, the FDA expanded the use of HIBERIX, allowing the vaccine to be the primary three-dose Hib series in children as young as six weeks of age.

In 2018, the FDA licensed MSP Vaccine Co.’s trademarked VAXELIS (manufactured by Merck & Co., Inc., and distributed by Merck, Sharp & Dohme LLC). VAXELIS is a hexavalent (6-in-1) vaccine that combines the 3-in-1 diphtheria, tetanus, and pertussis (DTaP) vaccine; the inactivated polio (IPV) vaccine; the hepititus B (HepB) vaccine; and the Hib vaccine for use as a three-dose series in infants at ages two, four, and six months. 

As we can see from this abbreviated history, a parade of Hib vaccines has come and gone.

The US currently has five Hib vaccines available for use: ActHIB, HIBERIX, PedvaxHIB, Pentacel, and VAXELIS. Each has its own set of problems, which we will enumerate below.

Problems with the Five Hib Vaccines

1. ActHIB (a monovalent vaccine manufactured by Sanofi Pasteur Inc.)

The Hib vaccine ActHIB was licensed based on trials with no placebo control group. Instead, a hepatitis B vaccine was used as the control. The safety review from one study revealed that 50 of the 1,455 participants (3.4%) experienced a serious adverse event 30 days post-injection, and yet “none was assessed by the investigators as related to the study of vaccines.” 

The impossibility of an accurate and comprehensive assessment of ActHIB’s safety and efficacy is compounded by the common practice of underpowered studies that have little-to-no long-term follow-up on trial subjects. Then there is the confounding problem that multiple other vaccines are tested on the subjects during the same trials.

A 1994 study found:

[The] combination with the Hib vaccine comprising polysaccharide conjugated to tetanus toxoid (the mechanism involved with ActHIB) had dramatic effects on tetanus potency and immunogenicity when assayed in mice. This combination resulted in a five-fold potentiation of the tetanus potency and a similarly large increase in the antibody responses to tetanus toxin and toxoid. [Emphasis added.]

Post-marketing side effects of ActHIB included “convulsions, anaphylaxis, peripheral edema, extensive limb swelling, pruritus, and rash.”

2. HIBERIX (a monovalent vaccine manufactured by GlaxoSmithKline Biologicals)

Like ActHIB, the Hib vaccine trademarked HIBERIX was licensed based on trials with no placebo controls. Instead, unlicensed Hib vaccines and HibTITER were used as controls. 

As we will remember, HIBERIX received accelerated approval. An honest appraisal of the benefits and/or safety of HIBERIX is virtually impossible: Evaluation is muddied by multiple vaccines given in conjunction with HIBERIX during the “trials,” making causal relations of reactions and cross-reactions unascertainable.

The HIBERIX package insert notes:

“In these 7 studies, HIBERIX was administered concomitantly with non-U.S. formulations (containing 2.5 mg 2-phenoxyethanol per dose as preservative) of one of the following U.S.-licensed vaccines: INFANRIX (DTaP) [Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed], KINRIX (DTaP-IPV) [Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed and Inactivated Poliovirus Vaccine], or PEDIARIX (DTaP-HBV-IPV). In the studies, DTaP-IPV and DTaP-HBV-IPV were administered in dosing regimens not approved in the U.S. Some subjects received DTaP-HBV (GlaxoSmithKline Biologicals, not licensed in U.S.) concomitantly with HIBERIX.”

Post-marketing adverse events for HIBERIX included extensive swelling of the vaccinated limb, injection site induration, allergic reactions (including anaphylactic and anaphylactoid reactions), angioedema, convulsions, hypotonic-hyporesponsive episodes, vasovagal syncope, apnea, rash and urticaria.

3. PedvaxHIB (a monovalent vaccine manufactured by Merck Sharp & Dohme Corp.)

PedvaxHIB, like ActHIB and HIBERIX, was licensed based on trials with no placebo controls. Instead, lyophilized (freeze-dried) PedvaxHIB was used as a control. 

In 2007, Merck announced a recall of specific vaccine lots of PedvaxHIB and its Hib-HepB combination vaccine Comvax, citing manufacturing issues. Merck discontinued production of Comvax in 2014.

Granted, lyophilized (freeze-dried) PedvaxHIB was tested in a trial in which the control groups were given a placebo, but there is no indication that lyophilized PedvaxHIB was ever licensed.

Meanwhile, DTP and OPV vaccines were administered to most control subjects along with the PedvaxHIB vaccine that was being tested.

The PedvaxHIB trial could charitably be called underpowered: Only three days of safety review were available after injection. The unsurprising conclusion:

Adverse reactions during a three-day period following administration of the booster dose were generally similar in type and frequency to those seen following primary vaccination[.]

The researchers did not elucidate on what “generally similar in type and frequency to those seen following primary vaccination” refers to nor did they provide citations with further details.

Possible side effects of PedvaxHIB included upper respiratory infection, seizures, tracheitis, thrombocytopenia, urticaria and post-marketing side effects included lymphadenopathy, febrile seizures, angioedema, and injection site abscesses.

4. Pentacel (a pentavalent [5-in-1] vaccine manufactured by Sanofi Pasteur Ltd.)

The 5-in-1 Hib vaccine was the first injection to administer five vaccines from a single needle. Hib vaccines began to be licensed in Canada in 1986. One of the earliest Hib vaccines was licensed and commercially introduced in Ontario in 1994 under the trade name PENTA (DPT-Polio-Hib PRP-T). This pentavalent injection was produced by Connaught Laboratories Ltd., the North American arm of Institut Mérieux of France (which was later bought by Aventis Pasteur and is now owned by Sanofi Pasteur).

PENTA produced an “immediate flood” of adverse events reported to Health Canada. The number and severity of these events was so pervasive and extreme that it resulted in the formation of the PENTA Project, a group of Canadian parents whose children had had been harmed by the PENTA vaccine.

The PENTA Project cataloged over 1,200 pages of adverse events:

An average of 300 adverse reports a month with a death every other month following immunization with PENTA were delivered to Health Canada.

After years of requests to and correspondences with the government and health officials, the Canadian Biologics and Genetic Therapies director admitted that PENTA had not been through the standard licensing procedure and did not have a Drug Identification Number (DIN) or a Notice of Compliance.

Only one study of the PENTA combination was referenced by Canada’s National Advisory Committee on Immunization in its supplementary statement for the newly licensed 5-in-1 injection. All 440 infants enrolled in that study received five vaccines in either one injection or in separate injections. 

Titled “Safety and immunogenicity of Haemophilus influenzae vaccine (tetanus toxoid conjugate) administered concurrently or combined with diphtheria and tetanus toxoids, pertussis vaccine and inactivated poliomyelitis vaccine to healthy infants at two, four and six months of age,”the study was funded by the manufacturer of PENTA, Connaught Laboratories Ltd. 

It is worth noting that during the study of PENTA “[n]urses were authorized to extend follow-up for 7 to 10 days by telephone or home visit if severe adverse events occurred.” 

Red flags were scattered throughout the study: 

“Thirteen infants were withdrawn from the study: . . . 1 because of maternal request following adverse symptoms after dose 2; 1 because of physician request after inconsolable crying following dose 1; 1 because of developmental delay with onset unrelated temporally to vaccination; and 3 after severe adverse events leading to hospitalization within 48 hours of vaccination.

“Three severe adverse events temporally associated with vaccination resulted in hospitalization; (1) an infant (Group C2) developed supraventricular tachycardia 48 hours after Dose 1 which responded promptly to digoxin therapy; (2) an infant (Group S1) was hospitalized after waking 3 hours after Dose 1 with cough, respiratory distress and cyanosis. Recovery occurred within 4 hours. Aspiration or gastro-esophageal reflux was suspected; (3) an infant (Group S2) was hospitalized after an episode of screaming with apnea or breath-holding 4 hours after Dose 1.”

In 2004, a report released by the Canadian Department of Pediatrics acknowledged:

Significant side effects were observed after Penta vaccination, commonly blamed on the whole cell pertussis component. Penta was also only about 60–80% effective against pertussis. Penta was not used in persons older than 7 years of age because the side effects are more severe in older persons. 

“In 1997, the whole cell pertussis was replaced throughout Canada by the acellular vaccine, combined with the same other components. This combination vaccine was given the name Pentacel, and is the current one used in infants.” [Emphasis added.]

All subsequent 5-in-1 vaccines, including Sanofi Pasteur’s Pentacel, are based on the same combination of components.

In 2008, Pentacel received licensure in the United States. The FDA’s Center for Biologics Evaluation and Research (CBER) conducted a clinical safety review that was based on four pivotal safety studies, including the Canadian study. Its Executive Summary states:

The Pentacel BLA [Biologics License Application] included safety data from four pivotal studies, in which a total of 5,980 subjects received at least one dose of Pentacel. Of these subjects, 4,198 were enrolled in one of three U.S. studies [. . .] that evaluated four consecutive doses of Pentacel administered at 2, 4, 6 and 15–16 months of age. [In the fourth study] conducted in Canada, 1,782 subjects previously vaccinated with three doses of Pentacel, received a fourth dose at 15–18 months of age.

The Executive Summary goes on to say:

“In two pivotal studies, the safety of Pentacel was compared to separately administered vaccines: HCPDT (DTaP manufactured by Sanofi Pasteur Limited; not licensed in the U.S.), POLIOVAX [. . .] and ActHIB [. . .] and DAPTACEL [. . .] and IPOL [. . .]. 

“In the three pivotal safety studies in which subjects received four consecutive doses of Pentacel, Prevnar [made by Wyeth Pharmaceuticals Inc.] was administered concomitantly with the first three doses of Pentacel in most subjects. The second and third doses of the hepatitis B vaccine series, using RECOMBIVAX HB [. . .] also were administered concomitantly with the first and third doses of Pentacel in most subjects. In one study, some subjects who had not previously received the first dose of hepatitis B vaccine received three doses of RECOMBIVAX HB concomitantly with the first three doses of Pentacel.”

In addition to safety data from these four pivotal studies, the BLA included supportive safety data from eight historical non-independent studies (six studies conducted in Canada and one each in Israel and Mexico). None of these studies included a control group that received a US-licensed DTaP vaccine or HCPDT.  

The BLA also included post-marketing safety data on Pentacel, reflecting a nine-year period between 1997 and 2006, during which a total of approximately 13.5 million doses of Pentacel were distributed outside the US—92% of those from Canada.

During that nine-year period, there were 14 post-marketing reports of deaths, including five cases of SIDS, four other deaths without known cause, two deaths due to Hib meningitis following the first dose of Pentacel, and one death each due to Group B streptococcal sepsis, congenital anomalies, and seizures. 

For all 14 reported deaths, the interval after the vaccination was between one day and 25 days. 

The Executive Summary concludes:

[T]he available safety data from the pivotal clinical studies and the supportive safety data from historical studies and from post-marketing use of Pentacel, primarily in Canada, support the safety of Pentacel in children 6 weeks to 4 years of age. [Emphasis added.] 

The Hib pentavalent vaccine saga was not confined to North America.

In March 2012 an open letter titled Pentavalent vaccine-related deaths in India” was sent by the All India Drug Action Network (AIDAN) to World Health Organization (WHO) Director-General Margaret Chan. Its seven authors cited several pentavalent vaccine-related deaths in India and neighboring South Asian countries:

As you would know, there have been several Pentavalent vaccine related deaths in Sri Lanka, Bhutan and Pakistan. Using the WHO-approved classification of AEFI [adverse events following immunization], many of these deaths are ‘probably related to the immunization’ because no alternate cause for the adverse events has been found. However, an expert panel looking at the deaths in Sri Lanka deleted ‘probably related’ and ‘possibly related’ from the classification of Brighton for purposes of their evaluation report, and then certified that the vaccines were ‘unlikely to be due to the vaccines.’

The letter’s authors pointed out that “[o]ne by one the WHO has delisted a number of brands of prequalified Pentavalent vaccine[s], but the problem has refused to go away”—which, they said, “suggest[s] that the cause of the problem was unrelated to the brand or manufacturer or lot of the vaccine.” 

In their conclusion, the seven authors observed that the pentavalent vaccine was being recommended at the time by WHO and that its introduction was supported by GAVI, whose founding partner is The Bill & Melinda Gates Foundation.

A warning about the hazards of pentavalent vaccines in India had been made at least two years earlier by one of the letter’s authors but was apparently ignored by public health authorities. In July 2010, Dr. Jacob Puliyel, head of the Department of Pediatrics at St. Stephen’s Hospital in Delhi, and colleague Zubair Lone wrote an editorial, “Introducing pentavalent vaccine in the EPI in India: A counsel for caution,” for the Indian Journal of Medical Research.

Puliyel and Lone harkened back to the 2009 swine flu scandal, reminding readers:

“The story of how pharmaceutical companies influenced scientists and official agencies like the World Health Organization (WHO) in the recent swine flu scare and the saga of the undeclared conflicts of interests of members of the WHO’s Strategic Advisory Group of Experts has set off alarm bells around the world. When trusted advisors are less than honest, the potential for harm is great, and the feeling of betrayal is poignant.”

Their editorial cited the “deaths as side effect” observed after use of the Hib vaccines in Sri Lanka and Bhutan:

“Pentavalent vaccine was introduced in the national immunization programme in Sri Lanka in January 2008 but after several thousand doses were administered, it was withdrawn in April 2008 because of 25 serious adverse reactions that included 5 deaths. 

[. . .]

“Pentavalent vaccine was then introduced in national immunization programme of Bhutan in July 2009. Within 2 months, after 8 deaths, the vaccine was withdrawn in that country.” 

Separately, in a July 2010 letter, “‘Sudden Deaths’ after Pentavalent vaccination: Is the vaccine really safe?,” published in the British Medical Journal (BMJ), eminent Indian pediatrician S. K. Mittal echoed Puliyel’s concerns:

“I am a member of the group that filed the petition against the Pentavalent vaccine in the Delhi High Court. [. . .] I write [. . .] to provide new data on the deaths following Pentavalent vaccination in Asia; in Pakistan and Bhutan. There have been 3 deaths in Pakistan and 8 deaths in Bhutan following Pentavalent vaccination, besides the deaths in Sri Lanka.

“According to an expert on the committee investigating the Pakistan deaths, one child died within half an hour of receiving the vaccine and 2 others died within 12 to 14 hours. No alternate cause of death was found for any of the deaths but the experts misleadingly suggest that ‘two cases were diagnosed as Sudden Infant Death Syndrome (SIDS) but we (the experts) were not sure of the third case.’ Yet in no case was the vaccine blamed for the deaths.

“The ‘expert report’ on the 8 deaths in Bhutan is not available in the public domain as far as we can ascertain. 

[. . .]

“It seems that no effort has been made to follow the WHO protocol for classification of adverse events following immunization (AEFI) in Pakistan or Bhutan. All the cases of sudden death following vaccination would have been classified as ‘Very likely’ or ‘Probably’ related to the vaccine if the standard AEFI classification were employed. This large cluster of ‘sudden death’ in Asia, following immunization with Pentavalent vaccine, needs to be investigated dispassionately before more lives are lost.”

On May 4, 2013, the Vietnam Ministry of Health suspended Quinvaxem, a pentavalent combination vaccine used in that country, after it had caused 12 deaths and nine non-fatal serious adverse events. 

Why the imperative for five vaccines inside one needle in the face of such clear and present danger to children’s lives? 

One answer may lie in a 2013 Indian Journal of Medical Ethics editorial written by the aforementioned Jacob Puliyel. Titled “AEFI and the pentavalent vaccine: looking for a composite picture,” his editorial seems to imply that the 5-in-1 Hib vaccine was a way for vaccine manufacturers to exploit India’s Universal Immunization Programme (UIP), which promotes adding more vaccines.

Dr. Puliyel wrote:

The Global Alliance for Vaccines and Immunisations (GAVI) and WHO recommended the use of this [Quinvaxem] pentavalent vaccine in developing countries to replace the DPT vaccine. The underlying reason (as described on the GAVI website) was to be able to increase the uptake of the hepatitis B and Hib vaccines in these countries by piggybacking these on a well-accepted vaccine.

His suspicions sound similar to those expressed in a 2006 Current Science Opinion piece titled “New combination vaccines: backdoor entry into India’s universal immunization programme?” and written by Madhavi Yennapu from the National Institute of Science and Technology and Development Studies:

[A] cursory glance at the new combination vaccines that are currently available in the Indian market reveals that virtually all of them have combined at least one universally administered vaccine with other non-UIP vaccines (Table 1). This is what raises suspicion that private vaccine manufacturers are using the combination vaccines as a means to push non-UIP vaccines into the UIP through the backdoor.

5. VAXELIS (the first and only hexavalent [6-in-1] vaccine, manufactured by MSP Vaccine Co., a US-based partnership of Merck & Co. and Sanofi)

The pharmaceutical industry’s insatiable appetite for multivalent vaccines didn’t stop with 5-in-1 injections. If pentavalents work, why not license hexavalents, too?

That is just what the FDA did in 2018, when it approved the 6-in-1 VAXELIS, the first hexavalent vaccine sanctioned for use in the US. The European Union (EU) had given the green light to the Merck-Sanofi Pasteur joint-venture vaccine two years earlier. (The European partnership ended in 2016, shortly after the EU approval.)

The potential dangers of hexavalents were well documented long before EU and FDA approval, however.

A 2014 study published in Current Medicine and Chemistry and titled, “Sudden infant death following hexavalent vaccination: a neuropathologic study,” looked at a large number of sudden infant death syndrome victims to examine causal relationships between a previous hexavalent vaccination and SIDS. The authors cautiously concluded:

This study does not prove a causal relationship between the hexavalent vaccination and SIDS. However, we hypothesize that vaccine components could have a direct role in sparking off a lethal outcome in vulnerable babies. In conclusion, we sustain the need that deaths occurring in a short space of time after hexavalent vaccination are appropriately investigated and submitted to a post-mortem examination particularly of the autonomic nervous system by an expert pathologist to objectively evaluate the possible causative role of the vaccine in SIDS.

Ten years earlier, a 2004 study published in the European Journal of Pediatrics and titled “Sudden and unexpected deaths after the administration of hexavalent vaccines (diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B, Haemophilius influenzae type b): is there a signal?” noted:

“[D]eaths in temporal association with vaccination of hexavalent vaccines have been recently reported.”

The authors warned that, while a definitive causal relationship between vaccination and SIDS was not established, the findings nonetheless . . .

“. . . constitute a signal for one of the two hexavalent vaccines which should prompt intensified surveillance for unexpected deaths after vaccination.”

A year after that study came a 2005 study, “Sudden infant death syndrome (SIDS) shortly after hexavalent vaccination: another pathology in suspected SIDS?,” which reported the case of a 3-month-old female infant who died suddenly and unexpectedly shortly after being given a hexavalent vaccination. The study authors wrote:

[T]his case offers a unique insight into the possible role of hexavalent vaccine in triggering a lethal outcome in a vulnerable baby.

They noted that test panels did examine the possible linkage between hexavalent vaccines and SIDS but did not look at “brainstem and the cardiac conduction systems on serial sections, [or the] possibility of a triggering role of the vaccine in these deaths considered.”

The following year, a 2006 study, “Unexplained cases of sudden infant death shortly after hexavalent vaccination,” reported several cases of SIDS in temporal relation to receiving the hexavalent vaccine. The authors wrote:

Prior to the release of hexavalent sera (in the years 1994–2000), we observed only one child out of 198 cases with sudden unexplained infant death who died shortly after vaccination (DTP). However, between 2001 and 2004, five such cases were identified in our institution [the Munich Institute of Legalized Medicine] among 74 children with SID[S]. This would indicate a 13-fold increase [in SIDS after the release of hexavalent injections]. 

In two US pre-licensing clinical trials (3,392 in the VAXELIS group and 889 in the control group, using Pentacel as the control) cited in the VAXELIS package insert, six deaths were reported in infants who received VAXELIS, and one death was reported from a participant who received Pentacel. Even though all six infants died within a month and a half of vaccination, none of the deaths were “assessed as vaccine related.” The causes of death given were sepsis, two cases of SIDS, asphyxia, an unknown cause, and hydrocephalus.

In 2019, ACIP voted to include the 6-in-1 DTaP-IPV-Hib-HepB vaccine in the federal Vaccines for Children Program (VFC) for use as a 3-dose series in infants ages 2, 4, and 6 months.

Widespread distribution of VAXELIS in the United States began in 2021. Around the same time, health economists were speaking about the need to place more combination vaccines in the market as a way to overcome vaccination rates that “are only expected to grow slowly” and that could not compensate for a declining childhood population.

According to analysts, VAXELIS “is expected to garner significant patient share following its launch due to benefits such as reducing shot-burden for infants and increasing the likelihood of adhering to vaccination schedules.” The 6-in-1 vaccine was expected to account for almost one-third of all DTaP vaccinations in the US by 2028 and to have annual sales of $841 million in the US by 2028. 

To date, no studies have been done on the combined impacts of the various antigens found in the Hib combination vaccines nor have these combinations ever been evaluated for their carcinogenic or mutagenic potential.


The next installment, Part 5 of our 14-part series, examines the Pneumococcal vaccines.