Are there vaccine ingredients which may not be disclosed ("hidden", "trade secret", or similar)?

Question

I sometimes encounter people claiming that there are ingredients in vaccines that can be kept secret by the manufacturer. I would be surprised to hear this, because the manufacturers have to conduct studies which show that the vaccine is safe. How to credibly present a study without showing what was tested seems difficult to me. However, I am not a clinician and I don't know the process in detail, so I would not detect possible loopholes.

A Google search for "impfstoff betriebsgeheimnis" (in German) yielded several results from known anti-vaccination websites (impfen-nein-danke.de, impffrei.at, impfkritik.de etc.). However, most of these sites just reiterate the claim without any justification or source. The only further information I could find is the following anecdote from the site gesundheit-natuerlich.at, first published there on Sep 28th, 2013

Das Paul-Ehrlich-Institut (PEI) ist für die Zulassung von Impfstoffen zuständig. Frau Anita Petek-Dimmer hat beim PEI telefonisch über die Inhaltsstoffe des Hepatitis-B-Impfstoffes nachgefragt. […]
The Paul-Ehrlich-Institute (PEI) is in charge of approving vaccines. Ms. Anita-Petek-Dimmer called them to ask about the ingredients of the vaccine against Hepatitis B.

Auf den Vorhalt, dass das PEI diesen Impfstoff zugelassen habe und er somit wissen müsse, was für Substanzen in diesem Impfstoff seien, […] antwortete [er], […] darüber stehe nichts in diesen Akten.
She told him that the PEI approved this vaccine and hence the PEI should know the ingredients. He replied that the documents don't contain this information.

Auf die Frage, wie denn dieser Impfstoff zugelassen werden könne, wenn das PEI nicht wisse, was drin sei, sagte dieser Herr, das verberge sich alles hinter dem Betriebsgeheimnis. Der Impfstoffhersteller sei nicht verpflichtet, der Zulassungsbehörde mitzuteilen, welche Substanzen im Impfstoff enthalten seien.
She asked how the vaccine can be approved without knowing the ingredients. The man from PEI replied, that the ingredients are a trade secret. The vaccine manufacturers are not obliged to disclose the ingredients of the vaccine to the authorities.

Anita Petek-Dimmer has had connections to other people who are known to spread nonscientific information. Other than that, I can not verify or debunk whether the story took place as described.

I have also found this website that says (emphasis added):

The FDA does not require vaccine manufacturers to make public every ingredient in a vaccine - some [vaccine ingredients] may be kept secret. This is documented on page 71 and page 77 of the 6th edition of the textbook Vaccines by Plotkin, Orenstein and Offit:

Questions:

• Are there vaccine ingredients which may not be disclosed ("hidden", "trade secret", or similar)?

• "The requirements and procedures for marketing authorisation, as well as the rules for monitoring authorised products, are primarily laid down in Directive 2001/83/EC and in Regulation (EC) No 726/2004" Searching these two directives for the term "ingredient" did not yield any result like "the manufacturer must provide a list of ingredients". Which law defines the things that a manufacturer of a medicinal product must disclose to the authorities?

• Sometimes real problems get retold and exaggerated to become a myth. Was there a change in legislation or a scandal which could explain why this story emerged? Was there a gap which is maybe now closed?

Answer 1

TL;DR: In the US and the EU, vaccine manufacturers are required to disclose all ingredients within the vaccine on vaccine packaging inserts available online alphabetically and European public assessment reports searchable through a database, respectively. In both regions, quantities of some ingredients (active ingredients, adjuvants, and absorbents) must also be disclosed. However, the US requires disclosure of all quantities of all vaccine ingredients while the EU doesn't.

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For the US, Title 21 of the Code of Federal Regulations mandates that for all biological products (which include vaccines), the packaging insert must contain information on all preservatives, antibiotics, inactive ingredients, adjuvants, and microorganisms. Packaging inserts are available directly from the FDA for all FDA approved vaccines. Thus, ingredients in vaccines cannot be kept secret. All ingredients are either of an active ingredient (microorganisms), inactive ingredient, or additive (preservatives, antibiotics, adjuvants) and must be labelled.

As an example, consider Dengvaxia, a vaccine intended to prevent dengue fever and also the most recent FDA approved vaccine¹. The packaging insert is available here. All ingredients are listed under Section 11 - Description (page 13 of the linked pdf).

After reconstitution with 0.6 mL 0.4% sodium chloride, 0.5 mL of the dose contains 4.5 - 6.0 log₁₀ CCID₅₀ (cell culture infectious dose 50%) "of each of the chimeric yellow fever dengue (CYD) virus serotypes 1, 2, 3, and 4. Each 0.5 mL dose is formulated to contain 2 mg sodium chloride and the following ingredients as stabilizers: 0.56 mg essential amino acids (including L-phenylalanine), 0.2 mg non-essential amino acids, 2.5 mg L-arginine hydrochloride, 18.75 mg sucrose, 13.75 mg D-trehalose dihydrate, 9.38 mg D-sorbitol, 0.18 mg trometamol, and 0.63 mg urea."

In addition to just the ingredients, information on culturing of the virus is also available.

Each of the four CYD viruses ( CYD-1, CYD-2, CYD-3, and CYD-4) in DENGVAXIA was constructed using recombinant DNA technology by replacing the sequences encoding the pre-membrane (prM) and envelope (E) proteins in the yellow fever (YF) 17D204 vaccine virus genome with those encoding for the homologous sequences of dengue virus serotypes 1, 2, 3, and 4, respectively. Each CYD virus is cultured separately in Vero cells ( African Green Monkey kidney) under serum-free conditions, harvested from the supernatant of the Vero cells and purified by membrane chromatography and ultrafiltration. The purified and concentrated harvest of each CYD virus is then diluted in a stabilizer solution to produce the four monovalent drug substances. The final bulk product is a mixture of the four monovalent drug substances diluted in the stabilizer solution. The final bulk product is sterilized by filtration at 0.22 μm, filled into vials and freeze-dried.

And finally, per Title 21, we are also informed "DENGVAXIA does not contain preservative." A separate CDC regulation stipulates specification of rubber type. In this case, it is synthetic rubber.

Are there vaccine ingredients which may not be disclosed (“hidden”, “trade secret” or similar)

No, all vaccine ingredients must be disclosed in the packaging insert of the vaccine. Quantities of all ingredients must also be disclosed. This differs from the EU law (demonstrated later).

Which law defines the things that a manufacturer of a medicinal product must disclose to the authorities?

In the US, Title 21, Volume 7, Chapter I, Subchapter F, Part 610, Subpart G, Sec. 610.61 of the Code of Federal Regulations.

Was there a change in legislation or a scandal which could explain why this story emerged? Was there a gap which is maybe now closed?

The earliest version of the law I could find was in 1998. The relevant section is here on pages 23 and 24. The wording of the law appears to be extremely similar as the current version. Before 1998, the last amendment to the law was in 1990 (see the bottom of this page). Thus, the reporting requirements were in place as early as 1990 and possibly even earlier.

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Title 21 of the Code of Federal Regulations

The following items shall appear on the label affixed to each package containing a product:

• The preservative used and its concentration, or if no preservative is used and the absence of a preservative is a safety factor, the words "no preservative";

• The type and calculated amount of antibiotics added during manufacture;

• The inactive ingredients when a safety factor, or reference to an enclosed circular containing appropriate information;

• The adjuvant, if present;

• The source of the product when a factor in safe administration;

• The identity of each microorganism used in manufacture, and, where applicable, the production medium and the method of inactivation, or reference to an enclosed circular containing appropriate information;

According to Law.SE, all inactive ingredients are listed. Additionally, I have contacted the FDA who provided similar information as I have already outlined in the answer.

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For the EU, Article 59 of Title V of Directive 2001/83/EC states (page 42 of the linked pdf):

1. The package leaflet shall be drawn up in accordance with the summary of the product characteristics; it shall include, in the following order:

   • (f) a reference to the expiry date indicated on the label, with:

   • • (iv) the full qualitative composition (in active substances and excipients) and the quantitative composition in active substances, using common names, for each presentation of the medicinal product;

Thus, all the name and quantity of all components of the vaccine must be published in the EU as well.

The European Medicines Agency has a separate document titled "Guideline on quality aspects included in the product information for vaccines for human use". Page 4 reads

The principal entries under Section 2 in the SmPC [summary of product characteristics] should appear in the following order:

• Qualitative and quantitative declaration of each active substance,
• Qualitative and quantitative declaration of any adjuvant or adsorbant present,
• Origin of the active substance, if applicable,
• Residues of clinical relevance, if applicable,
• Excipients with known effects, if applicable,
• a reference to the full list of excipients in 6.1,

Excipients are all components of a vaccine that are not active ingredients (e.g. preservatives, adjuvants, and stabilizers). As the quantity, type, and origin of active ingredients must be disclosed, we can conclude that the EU requires labelling of all ingredients within the vaccine. The linked pdfs also contain other more specific labeling guidelines.

The earliest version of the law that I could find was in 2001. The requirement to disclose all ingredients was still there (see page 36 and 37 of the linked pdf). However, I noticed fewer guidelines on reporting the risks of excipients (e.g. In 2001, manufacturers had to report all excipients, but manufacturers didn't have to report the known risks; now manufacturers have to do both).

In the EU, the European Medicines Agency is responsible for approving vaccines. A database of all approved medicines is here. A search specifically for human vaccines is here. As an example, consider the most recently approved non-flu vaccine in the EU, which is also Dengvaxia (authorized 12/12/2018). The authorization website contains various documents, including a 64 page European public assessment report. The report contains a list of excipients in Section 6.1 (page 15).

Powder:

• Essential amino acids including Phenylalanine

• Non-essential amino acids

• Arginine hydrochloride

• Sucrose

• Trehalose dihydrate

• Sorbitol (E420)

• Trometamol

• Urea

Solvent:

• Sodium chloride

• Water for injections

At first glance the sections of the report appears to be largely duplicated (e.g. pages 2 through 16 are largely duplicated again in pages 17 through 32). Confusingly, this is because half of it apply to Dengvaxia in pre-filled syringe while the other half apply to Dengvaxia in multidose containers.The packaging leaflet for the user (pages 49 through 56) contains the vaccine ingredients as well (page 53).

• After reconstitution, one dose (0.5 mL) contains 4.5 - 6.0 log10 CCID₅₀* of each serotype of the chimeric yellow fever dengue virus** (1, 2, 3 and 4) (live, attenuated).

• • CCID₅₀: 50% Cell Culture Infectious Dose.
• • Produced in Vero cells by recombinant DNA technology. This product contains genetically modified organisms (GMOs).

• The other ingredients are: essential amino acids including Phenylalanine, non-essential amino acids, Arginine hydrochloride, Sucrose, Trehalose dihydrate, Sorbitol (E420), trometamol, urea, sodium chloride, water for injections.

The reason I am listing this out is to show a major difference between EU and US laws. This is reflected in the European public assessment report (from the EU) and the packaging insert (from the US FDA). Excipients are listed for both situations but the concentration and volume (e.g. quantitative descriptions) are only listed for the packaging insert. The EU law requires disclosure of quantities of active ingredients, adjuvants, and absorbents. If an excipient is neither an adjuvant or absorbent (such as sodium chloride) the concentration and volume are not disclosed. This is reflected in the European public assessment report.

Are there vaccine ingredients which may not be disclosed (“hidden”, “trade secret” or similar)

No, all vaccine ingredients must be disclosed in the summary of product characteristics of the vaccine. Quantities of active ingredients, adjuvants, and absorbents must also be disclosed. Quantities of other ingredients need not be disclosed (and usually aren't). This is the biggest difference between the EU and the US laws.

Which law defines the things that a manufacturer of a medicinal product must disclose to the authorities?

In the EU, Article 59 of Title V of Directive 2001/83/EC.

Was there a change in legislation or a scandal which could explain why this story emerged? Was there a gap which is maybe now closed?

The earliest version of the law I could find was in 6 November 2001. I suspect this was the very first version of the law as the directive is "2001/83." The reporting requirements were in place as early as 2001.

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Note regarding the textbook image: The textbook mentioned in the claim in the question does indeed exist. Additionally, the underlined sentence is real. We can check this on Google Books. Page 77 of the book clarifies this.

The Food, Drug and Cosmetic Act (Section 502[e][1][A][iii]) states that all inactive ingredients should be noted in labeling; it also states that this requirement is not necessary if trade secret information would be disclosed. The CFR additionally notes that an inactive ingredient should be listed in the labeling if the ingredient's presence is considered a safety factor (21 CFR 610.61[n]). In some cases, even in the absence of any evidence that a particular material might pose a safety factor, manufacturers have elected to disclose the presence of residual materials such as detergents, solvents, and chelating agents (see Table 6-2 for examples of manufacturing residuals).

The CFR law has been quoted earlier. Following is the relevant excerpt from the Food, Drug, and Cosmetic Act (FD&C Act).

(iii) the established name of each inactive ingredient listed in alphabetical order on the outside container of the retail package and, if determined to be appropriate by the Secretary, on the immediate container, as prescribed in regulation promulgated by the Secretary, except that nothing in this subclause shall be deemed to require that any trade secret be divulged, and except that the requirements of this subclause with respect to alphabetical order shall apply only to nonprescription drugs that are not also cosmetics and that this subclause shall not apply to nonprescription drugs not intended for human use.

As I just dug up the textbook ~20 minutes ago, I do not have enough time to resolve this apparent contradiction in law. Potentially, the CFR and the FD&C Act can conflict when a trade secret prevents disclosure of an ingredient. I have asked this on Law.SE and will update this answer later.

My interpretation is: If the trade secret impacts safety, it must be disclosed. If the trade secret does not impact safety, it does not have to be disclosed. As such, the quote from the textbook "Some information regarding additives and residuals is considered to be a trade secret and thus confidential, and cannot be discussed in this chapter." is taken out of context. Such trade secrets can only be kept when there is no impact on safety. Again, I will update this answer later.

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¹Headline under FDA Official Releases: "FDA approves Dengvaxia, the first vaccine approved for the prevention of dengue disease in people ages 9 through 16 who have laboratory-confirmed previous dengue infection and who live in endemic areas." For those curious and interested, there is another news release here titled "First FDA-approved vaccine for the prevention of dengue disease in endemic regions."

Answer 2

The word ingredient isn't as straightforward as it seems. There are many substances that are present in vaccines that are listed on the packaging label. That makes it unlikely that the conversation took place as suggested in the question.

An ingredient is a functional substance that the manufacturer has put in on purpose and/or one that is defined as "has to be declared". A "content analysis" by eg gas chromatography may reveal more substances in it than on the label.

I'll address the example brought forward in the other answer by Barry Harrison:

Each of the four CYD viruses ( CYD-1, CYD-2, CYD-3, and CYD-4) in DENGVAXIA was constructed using recombinant DNA technology by replacing the sequences encoding the pre-membrane (prM) and envelope (E) proteins in the yellow fever (YF) 17D204 vaccine virus genome with those encoding for the homologous sequences of dengue virus serotypes 1, 2, 3, and 4, respectively. Each CYD virus is cultured separately in Vero cells ( African Green Monkey kidney) under serum-free conditions, harvested from the supernatant of the Vero cells and purified by membrane chromatography and ultrafiltration. The purified and concentrated harvest of each CYD virus is then diluted in a stabilizer solution to produce the four monovalent drug substances. The final bulk product is a mixture of the four monovalent drug substances diluted in the stabilizer solution. The final bulk product is sterilized by filtration at 0.22 μm, filled into vials and freeze-dried.

This description omits how the Vero cells were fed which is clinically relevant information. If the Vero cells for example get fed egg protein and the purification process won't be perfect which results in Ovalbumin ending up in the final vaccine.

The production of sorbitol also isn't 100% pure and there's a good chance that proteins from food sources will end up in the final vaccine.

The Institute of Medicine wrote in 2011 a report that suggests that those kinds of proteins exist in vaccines that are on the market in a quantity that might have negative clinical implications:

Adverse events on our list thought to be due to IgE-mediated hypersensitivity reactions Antigens in the vaccines that the committee is charged with reviewing do not typically elicit an
immediate hypersensitivity reaction (e.g., hepatitis B surface antigen, toxoids, gelatin, ovalbumin, casamino acids). However, as will be discussed in subsequent chapters, the above-mentioned antigens do occasionally induce IgE-mediated sensitization in some individuals and subsequent hypersensitivity reactions, including anaphylaxis”

Unfortunately, the FDA neither forces manufacturers to disclose the levels of the residual antigens nor sets limits:

I was able to confirm with the Food and Drug Administration (FDA), the United States Pharmacopeia (USP) and vaccine maker Sanofi Pasteur that there are no specifications limiting allergen content in vaccines approved for use in the United States. In other words, no safe level has been established or enforced for allergens contained in vaccines. Vaccine excipient makers such as sorbitol, Polysorbate 80 manufacturers also have no limits on residual allergens in their injectable grade products. Since there are no limits, suppliers do not test for allergens in production. Further, residual allergens that may be present in the excipients are not even listed in the vaccine package inserts.

That said, there are considerable health benefits of vaccinations that are not canceled out that by the small risk to develop allergies that comes from the impurities of the vaccine manufacturing process.

Answer 3

The statement in another answer that common allergens (like ovalbumin) are not labelled or measured in vaccines is specific to the US. Since the Q is about the EU as well, I'm fairly certain that some testing and labelling is required or at least strongly recommended for such trace products. For example, the EMA info for a flu vaccine says:

The vaccine may contain residues of the following substances: egg proteins (e.g. ovalbumin) and gentamicin. The maximum amount of ovalbumin is less than 0.024 micrograms per 0.2 ml dose (0.12 micrograms per ml).

There is certainly an EMA document that suggest this should be done:

Process related impurities (e.g. ovalbumin for egg-derived influenza vaccine / host cell protein, residual host cell DNA for cell culture-derived vaccine, downstream-derived impurities such as reagents used for inactivation/splitting) should be identified, quantified and data used to set release specifications.

There are also country-specific guidelines like these from the UK on how to use such vaccines:

The Joint Committee on Vaccination and Immunisation has advised that, except for those with severe anaphylaxis to egg, which has previously required intensive care, children with an egg allergy can be safely vaccinated with the live attenuated influenza vaccine (Fluenz Tetra); those with clinical risk factors that contraindicate Fluenz Tetra should be offered an inactivated influenza vaccine with a very low ovalbumin content (<0.12 μg/mL).

In adults, the ovalbumin-free influenza vaccine (Optaflu), if available, can be used in any setting, regardless of the severity of the egg allergy. Adult patients can also be immunised in any setting using an inactivated influenza vaccine with an ovalbumin content <0.12 μg/mL, except those with severe anaphylaxis to egg that has previously required intensive care.

There's also a 2014 book with this summary table (which includes ovalbumin), which suggests that the WHO drew up some recommendations in 2005 and the EU adopted some (stricter ones) in 2012. No mention of US though:

Corroborating with another source that cites the 2005 WHO Technical Report Series No. 927, the ovalbumin limit in that table is per dose (rather than per ml as in earlier quotes).

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On another angle, the red-underlined quote is pretty misleadingly interpreted. "Some information regarding additive and residuals is considered to be a trade secret." Sure, "some information". But what that means in practice is more like some process details, and sometimes some clinical data (the last point is the most contentious), e.g.

For example, when immense public pressure led to the release of US vaccine contracts in November 2020, the public learned that the Johnson & Johnson contract explicitly allowed the company to keep secret “production/manufacturing know-how, trade secrets, [and] clinical data.”

Also, even regarding US requirements for sensitizing substances reporting, the 2nd source quoted by Christian's answer seem pretty dubious (single author with no academic or industry affiliation, publishing in an obscure journal... a bunch of their publications are just plain linking vaccines to autism) and it is the one making the bold claims that allergens in US vaccines are not reported (it's actually citing the author's personal communications with officials for that). The very same book from which the misleading red-underlined quote was taken says much more, but not exactly backing that author up:

The CFR’s biologics labeling regulations (21 CFR §610.61[l]) provide that “known sensitizing substances” should be listed on the product label. Furthermore, 21 CFR §610.15(b) states that “extraneous protein known to be capable of producing allergenic effects in human subjects shall not be added to a final virus medium of cell culture produced vaccines intended for injection.” These regulations address the possibility that animal-derived proteins present in the final formulation of a vaccine can cause allergic reactions in some vaccine recipients. (Other sensitizing substances, such as preservatives, are addressed in other sections of these regulations.) Animal- derived materials are used extensively in vaccine manufacturing, particularly in viral cultures. When viral vaccines are grown in embryonated chicken eggs (influenza and yellow fever vaccines) or chick embryo cell culture (measles or mumps virus vaccines), the label will state that residual chicken proteins may be present in the final formulation (see Table 7.2). Although hypersensitivity to any component of the vaccine is a contraindication, the MMR-II and yellow fever vaccine (YF- Vax) package inserts address the vaccination of persons with hypersensitivity to eggs or egg protein.

The two U.S.-licensed hepatitis B vaccines, Engerix-B (Glaxo- SmithKline Biologicals) and Recombivax HB (Merck Sharpe & Dohme Corp.), are recombinant DNA–derived proteins and are produced in yeast; their package inserts note that residual yeast protein may be present (Engerix-B contains not more than 5% and Recombivax HB not more than 1% yeast protein). Hepatitis B vaccine is contraindicated in persons with a history of hypersensitivity to yeast; however, the ACIP has noted that “no evidence exists that documents adverse reactions after vaccination of persons with a history of yeast allergy.” The HPV vaccines, Gardasil (Merck Sharp & Dohme Corp.) and Gardasil 9 (Merck Sharp & Dohme Corp.), are also manufactured in yeast cells; according to the package inserts, both vaccines contain less than 7 μg of yeast proteins per dose; hypersensitivity to yeast is given as a contraindication to receiving the vaccine. The other HPV vaccine, Cervarix (Glaxo- SmithKline Biologicals), is manufactured in insect cells; levels of insect cell proteins are reduced to less than 40 ng/dose.

There's a two-page table which follows, but I'm going to post just the part on influenza vaccines (as those are actually not discussed in the above quote, and while the table does a lot more detail on those included in the text above... the table-level of detail is on par with that for influenza ones.)

One of the tree egg-grown vaccines in that table (Fluzone) indeed doesn't seem to report ovalbumin contents, but the other two (Afluria, Fluarix) do report it. (I haven't investigated further why there is this discrepancy.)

As with other things related to medication approval (despite some people's wishes) there cannot be an entirely cookbook approach to these. It's clear from the above that despite the lack of strictly spelled out law/regulation requirements (like levels), the US regulators in conjunction with the manufacturers have provided sensible info on sensitizing substances in vaccines... the reporting of which is actually mandated in general terms in the federal regulations. If there's something that's indeed spelled out as usually not reported (in the US)... that's DNA and endotoxins:

Bacterial and viral inactivation substances must be noted in the package label (21 CFR §610.61[q]). Residual bacterial or cellular culture components, such as antibiotics that are used during manufacture, as well as sensitizing substances (generally proteins), and other inactive ingredients when considered a safety factor, also must be noted in the label (21 CFR §610.61 [l][m][n]). There may be some overlap between these categories; however, they are grouped in this manner for convenience and to aid a discussion of these materials as they are affected by current regulations. Residual bacterial or cell culture components may be included in these categories, but other residuals, such as DNA and endotoxin, are not generally noted in labeling.