How are vaccines evaluated for safety?

A review of some Prevnar studies on InsideVaccines

*All data herein is from the manufacturer’s package inserts.

**All studies listed excluded children who weren’t healthy–roughly 60% of the general population of infants and children would not be accepted into a vaccine study.

***Vaccines are tested in animals first, but were not tested for toxicity as they were presumed safe. Here is a link to the FDA/CDC discussion in 2002 regarding this topic (1).

Historically, the non-clinical safety assessment for preventive vaccines has often not included toxicity studies in animal models. This is because vaccines have not been viewed as inherently toxic, and vaccines are generally administered in limited dosages over months or even years.  (see page 11-12)

****See note at bottom of page regarding why the “placebos” in these safety trials aren’t usually placebos like saline or sugar water but other vaccines.


ActHib was tested for safety by giving one group ActHib w/ DTP and the control group was given Hep B w/ DTP.

From the package insert (page 7):

In a randomized, double-blind US clinical trial, ActHIB® was given concomitantly with DTP to more than 5,000 infants and Hepatitis B vaccine was given with DTP to a similar number.

In this large study, deaths due to sudden infant death syndrome (SIDS) and other causes were observed but were not different in the two groups.

In the first 48 hours following immunization, two definite and three possible seizures were observed after ActHIB® and DTP in comparison with none after Hepatitis B vaccine and DTP. This rate of seizures following ActHIB® and DTP was not greater than previously reported in infants receiving DTP alone. (Refer to product insert for AvP DTP.) Other adverse reactions reported with administration of other Haemophilus b conjugate vaccines include urticaria, seizures, hives, renal failure and Guillain-Barré syndrome (GBS). A cause and effect relationship among any of these events and the vaccination has not been established.

In summary, Group A received Hib and DTP (whole-cell pertussis vaccine, a highly reactive vaccine-no longer on the market in the US). Group B received Hepatitis B vaccine and DTP. Vaccine reactions were then compared between the two groups. Both groups reported SIDS deaths and seizures, but these seem to be attributed to the DTP as this had been previously reported for DTP vaccines. Additionally, none of the other adverse reactions that “coincidentally” surfaced in these previously healthy infants during this trial could be causally related to the vaccines. Based on this information, ActHib was judged safe.

Why would a vaccine manufacturer voluntarily give their vaccine at the SAME time as one of the most highly reactive? What would they have to gain from this? What would they have to lose?


Tripedia (DTaP) Sanofi Pasteur:
One group received Tripedia and the control group received Aventis’ whole cell DTP vaccine (page 6 of the package insert).

In a double-blind, comparative US trial, 673 infants were randomized to receive either 3 doses of Tripedia vaccine or AvP’s whole-cell pertussis DTP vaccine (Table 2).

Safety data are available for 672 infants, including 505 who received Tripedia vaccine and 167 who received whole-cell pertussis DTP vaccine. Following all three doses, rates for all reported local reactions, fever > 101°F, irritability, drowsiness, and anorexia were significantly less in Tripedia vaccine recipients. Reaction rates generally peaked within the first 24 hours, and decreased substantially over the next two days.2,27,28

A similar reduction in adverse events was seen in a randomized, double-blind, comparative trial conducted in the US by the NIH when Tripedia vaccine was compared to Lederle Laboratories whole-cell pertussis DTP vaccine.

DTaP is the acellular version of DTP. Whole cell pertussis vaccines were highly reactive and had to be modified. This study shows that the new DTaP vaccine is not as reactive as the (replaced) DTP. We would hope so. Does this, however, prove to parents that the DTaP is safe?

Infanrix (DTaP) Glaxo:
The control group was given DTP or there was no control group.

Approximately 92,000 doses of INFANRIX have been administered in clinical studies. In these studies, 28,749 infants have received INFANRIX in primary series studies, 5,830 children have received INFANRIX as a fourth dose following 3 doses of INFANRIX, and 511 children have received INFANRIX as a fifth dose following 4 doses of INFANRIX. In addition, 439 children and 169 children have received INFANRIX as a fourth or fifth dose following 3 or 4 doses of whole-cell DTP vaccine, respectively. In comparative studies, the first 4 doses of INFANRIX have been shown to be followed by fewer of the local and systemic adverse reactions commonly associated with whole-cell DTP vaccination.

In the double-blind, randomized comparative trial in Italy, safety data in a 3-dose primary series are available for 4,696 infants who received at least one dose of INFANRIX and 4,678 infants who received at least one dose of US-licensed whole-cell DTP vaccine manufactured by Connaught Laboratories, Inc. All common solicited adverse events were less frequent following vaccination with INFANRIX as compared to whole-cell DTP after each 1 of the 3 doses.


Gardasil (HPV) Merck: The Gardasil group had 5,088 subjects. The reason why I’m listing the number of subjects will be clear when you read the next few sentences.

The first control group received an aluminum-containing placebo (3,470 subjects). The second control group received a saline placebo (only 320 subjects). When comparing minor AE’s (adverse events), Merck compared data for both placebo groups, clearly showing which ones occurred in the saline group and which one occurred in the aluminum group. However, when comparing data for serious AE’s, Merck COMBINED the two placebo groups and then compared it to the Gardasil group.

They do not reveal the difference in serious AE’s between the aluminum placebo group and the saline group.

Why do we think this is important? What would it prove if the aluminum-containing placebo group had significantly higher serious AE’s than the saline placebo group; what would it prove if those numbers were more statistically reflective of the Gardasil group? What are the main ingredients in Gardasil? Is one of them aluminum?

Hep B

Energix B (Hep B) Glaxo
The control group received plasma-derived vaccines. The exact vaccines administered to the control are not revealed.

Ten double-blind studies involving 2,252 subjects showed no significant difference in the frequency or severity of adverse experiences between ENGERIX-B and plasma-derived vaccines.

In 36 clinical studies, a total of 13,495 doses of ENGERIX-B were administered to 5,071 healthy adults and children who were initially seronegative for hepatitis B markers, and healthy neonates. All subjects were monitored for 4 days post-administration.

Recombivax HB (Hep B) Merck
This vaccine was not evaluated for safety using a control group.

In three clinical studies, 434 doses of RECOMBIVAX HB, 5 mcg, were administered to 147 healthy infants and children (up to 10 years of age) who were monitored for 5 days after each dose.

In a study that compared the three-dose regimen (5 mcg) with the two-dose regimen (10 mcg) of RECOMBIVAX HB in adolescents, the overall frequency of adverse reactions was generally similar.

In a group of studies, 3258 doses of RECOMBIVAX HB, 10 mcg, were administered to 1252 healthy adults who were monitored for 5 days after each dose

Hmmm. So, those who received 3 doses had the same number of adverse effects as those who received 2 doses (after 5 days of being monitored). OR, they were compared to a mystery plasma-derived vaccine and showed no difference in adverse events. This passed muster and proved that Hepatitis B vaccines are safe.


MMR II Merck

The control group received a monovalent or bivalent vaccine containing measles, mumps, or rubella.

Basically, this was comparing the vaccine against itself. For example, Group A would have gotten MMRII and the control group would have gotten either a single measles shot, single mumps shot, single rubella shot or a combination of two.


Prevnar (Wyeth)

The majority of the safety experience with Prevnar comes from the NCKP Efficacy Trial in which 17,066 infants received 55,352 doses of Prevnar, along with other routine childhood vaccines through April 1998.

The “other routine childhood vaccine” was DTaP and control groups were given Meningitis C (conjugate) vaccine.


IPOL (Inactivated Polio) Sanofi

The inactivated polio vaccine was given at the same time as the DTP. Here are the findings:

Because IPV was given in a different site but concurrently with Diphtheria and Tetanus Toxoids and Pertussis Vaccine Absorbed (DTP), these systemic reactions could not be attributed to a specific vaccine. However, these systemic reactions were comparable in frequency and severity to that reported for DTP given alone without IPV.


*Author’s note: Many people raise the issue of the Declaration of Helsinki and its amendments in answer to these issues regarding placebo and safety studies. The Declaration prohibits the use of placebo control groups if there is already a “proven” treatment. (It is considered withholding treatment to use a placebo instead of the “approved” treatment.) Thus, you must only compare the “new” treatment to the “old” or existing treatment, when there is an “approved” treatment in place.  However, others interpret this to mean that placebos can be used in safety studies, but cannot in efficacy studies.

So, we are not seeing proof that x vaccine is safe. What these studies prove is that x vaccine is safer than the “other” vaccine.

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