New Generation of Vaccine Adjuvants: Worst Ever?

A new generation of vaccine adjuvants is being rolled out, literally mass produced. They’re touted as safe, but they share a dirty secret: They’re oil-based, which could make them the most dangerous yet in a product line that is, by definition, toxic.

by Heidi Stevenson

All vaccine adjuvants are, by definition, toxic. Their function is to stimulate the immune system, that is, to initiate a response to a toxic agent. So, a new generation of adjuvants is being promoted as less toxic than any that have come before, while at the same time doing an even better job of priming the immune system so it will react to weak antigens. This leads to the question of how an adjuvant can be both safer than previous adjuvants and also more capable of agitating the stronger immune system response required to promote antibody creation to weaker antigens.

These new adjuvants are made from outer membrane vesicles (OMVs). A vesicle is a cavity, or sac. In a bacterium, OMVs are sacs that protrude from the exterior—membrane—of its body to protect itself in hostile environments. An OMV’s function is to be toxic.

Recombinant DNA technology is used to engineer bacteria so that they make OMVs to be used as antigens or adjuvants, which are then processed and added to vaccines. All of these products that are grown on the surfaces of microbes have one thing in common: they are proteoliposomes:

A proteoliposome is a liposome with one or more proteins inserted.
A liposome is a minute spherical sac of phospholipid molecules enclosing a water droplet.
A phospholipid is a type of lipid.
A lipid is a fatty acid. That is, a lipid is a fat.

And that makes these new adjuvants, or antigens with adjuvants built in, particularly worrisome. Fats and oils are known to be exceptionally dangerous when injected. Their similarity to normal body tissues is the reason. Fats do not normally enter the body through injections. They are either digested or created by the body, in which case there’s no problem. However, injection is not a normal means for lipids to enter the body.

Therefore, an injected lipid can be seen by the immune system as an invader. Of course, the response to an invader is to create antibodies against it. Since lipids normally exist throughout the body, when the immune system is radicalized into seeing a lipid as the enemy, it’s attacked—wherever it’s found, even when it’s a normal part of the body.

That’s the definition of an autoimmune disorder: the body’s own immune system starts attacking itself.

It’s not a secret that injection of lipids causes autoimmune disorders. In fact, it’s so well known that lipid injection is a standard technique for creating autoimmune disorders in laboratory animals for study. In particular, the active ingredient in Freund’s adjuvant, a lipid, is used to create an analog of human rheumatoid arthritis in lab rats.

Yet, lipids, in the form of recombinantly-created OMVs, are being added to vaccines for injection into humans!

Why Move to OMV Adjuvants?

The push for OMV adjuvants is happening because vaccine antigens—the part of a vaccine that’s supposed to trigger an autoimmune response that results in antibodies—need to create a strong immune response. But that’s not an easy task unless the antigen is a live microbe, which could cause a full-fledged disease. That’s why weakened or killed microbes have traditionally been used.

However, such weakened and killed microbes are not easy to produce, nor can the process be hurried. It is, therefore, expensive and, in the case of influenza, can take too long to respond to an ongoing outbreak. So, the modern approach is to utilize bits of microbes, or better yet, to grow those bits through recombinant DNA, such as in tobacco plants. The problem with this method is that these protein bits don’t create much of an immune response. Therefore, since the old standard, aluminum, doesn’t accomplish the job well enough, stronger adjuvants are required to initiate that response.

That’s why there’s a rush to implement OMV antigens and adjuvants. Once the process for a particular antigen or adjuvant is worked out, it becomes a relatively inexpensive process to grow it on a large scale for vaccines.

At this point, there is one vaccine with an OMV adjuvant on the market, Cervarix. Its adjuvant is marketed as AS04. It contains aluminum and OMV-derived 3-O-desacyl-4’-monophosphoryl lipid A (MPL). You can see from the chemical name that MPL is a lipid.

OMV Adjuvant Safety?

Adjuvants were discovered by accident when it was noted that dirty—literally dirty, contaminated—vaccine containers produced better results in terms of a vaccine’s ability to create antibodies. It was literally the dirty secret of vaccinology, and led to the intentional contamination of vaccines. The contaminants were relabeled as adjuvants.

Of course, there are side effects to adjuvants. The one that became standard, aluminum, is a known toxin. But, as long as it made the vaccine more effective at producing antibodies, the toxic properties of aluminum were—and still are—swept under the rug.

Other adjuvants had been tried, but all were even more toxic. Among the very worst were ones based on oils, Freund’s adjuvants. These were quickly determined to be far too toxic for use in vaccines, though they did find another marketable use. Freund’s adjuvants are now routinely used in medical research because they create the equivalent of human autoimmune disorders, such as rheumatoid arthritis, in laboratory animals, which are then studied to find treatments for the human disorders.

Now they have found OMV adjuvants, which are being promoted as the safest yet. A recent report in Proceedings of the National Academy of Sciences (PNAS), discusses “a less toxic mixture of monophosphorylated lipid A species (MPL)” made through the OMV methodology. Notice that the emphasis is on “less toxic”.

The fallacious claim that OMV lipids are safe is based on their being natural. It’s that very fact, that they’re natural—literally analogs of normal body chemistry—that makes them so dangerous. Their injection can cause them to be seen as toxins—which, of course, in this context they are—which can result in antibodies being developed against chemicals that are naturally found in the body. An autoimmune disease is the body’s immune system turning on itself.

There is, though, a great deal of emphasis on OMV lipids’ ability to elicit a strong immune system response to create antibodies. Just how something can be less toxic, yet cause a stronger response to toxicity is not explored.

Apparently, it’s to be taken on faith that these lipids are safe, when all other lipids are too dangerous for use in humans. But where are the trials to prove it?

Slipping Around the Approval Process

The FDA has made clear that they don’t approve adjuvants. Their logic is that adjuvants are not produced for end users. They’re produced for use in products that go to end users. The FDA doesn’t focus on individual ingredients in medical products. So they approve vaccines that include adjuvants, thus evading the issue of adjuvants’ toxicity.

Obviously, you cannot run tests of products that are intended to do harm, which is the case with all vaccine adjuvants, and hope to demonstrate safety. So, you won’t see safety trials of them. It would, of course, be considered unethical.

But apparently not so unethical that there’s any reason to stop their use in vaccines.

OMV adjuvants are now being promoted as “designer bacteria”. They’re being touted as safe, yet better able to elicit a response from weak antigens—a process that, by definition, requires more toxic adjuvants, not less toxic ones.

So, are the new generation of OMV adjuvants the worst ever? Is there any reason to assume otherwise?

Of one thing we can be certain: We’ll find out on the bodies of our children. These adjuvants are now being rolled out in a big way. They’re the basis of the enormous number of vaccines in the pipeline.

Sources:

1. Modulating the innate immune response by combinatorial engineering of endotoxin, PNAS, Brittany D. Needham, Sean M. Carroll, David K. Giles, George Georgiou, Marvin Whiteley, andM. Stephen Trent
2. Bacterial outer membrane vesicles and the host–pathogen interaction, Genes and Development, Meta J. Kuehn and Nicole C. Kesty
3. Outer Membrane Vesicles Derived from Escherichia coli Induce Systemic Inflammatory Response Syndrome, PLoS One, Kyong-Su Park, Kyoung-Ho Choi, You-Sun Kim, Bok Sil Hong, Oh Youn Kim, Ji Hyun Kim, Chang Min Yoon, Gou-Young Koh, Yoon-Keun Kim, Yong Song Gho, doi:10.1371/journal.pone.0011334
4. Outer membrane vesicle of Neisseria meningitidis serogroup B as an adjuvant in immunization of rabbit against Neisseria meningitidis serogroup A, African Journal of Microbiology Research, Seyed Davar Siadat, Saied Reza Naddaf, Mehrangiz Zangeneh, Arfa Moshiri, Seyed Mehdi Sadat, Mehdi Shafiee Ardestani, Mohammad Hassan Pouriayevali, Safieh Amini, and Mohammad Reza Aghasadeghi. DOI: 10.5897/AJMR11.361
5. Briefing Materials for the Meeting of the Vaccines and Related Biological Products Advisory Committee, 7th April, 2011
6. Immunogenicity and Tolerability of Recombinant Serogroup B Meningococcal Vaccine Administered With or Without Routine Infant Vaccinations According to Different Immunization SchedulesA Randomized Controlled Trial, doi:10.1001/jama.2012.85
7. Delivery of foreign antigens by engineered outer membrane vesicle vaccines, PNAS, David J. Chen, Nikolaus Osterrieder, Stephan M. Metzger, Elizabeth Buckles, Anne M. Doody, Matthew P. DeLisa, and David Putnam
8. Outer membrane vesicle of Neisseria meningitidisserogroup B as an adjuvant to induce specific antibody response against the lipopolysaccharide of Brucella abortus S99
9. Contribution of bacterial outer membrane vesicles to innate bacterial defense, doi:10.1186/1471-2180-11-258
10. Analysis of outer membrane vesicle associated proteins isolated from the plant pathogenic bacterium Xanthomonas campestris pv. campestris, doi:10.1186/1471-2180-8-87
11. PorA Variable Regions of Neisseria meningitidis, Emerging Infectious Diseases
12. Restored functional immunogenicity of purified meningococcal PorA by incorporation into liposomes
13. Liposomal meningococcal B vaccination: role of dendritic cell targeting in the development of a protective immune response. Infection and Immunity, doi: 10.1128/IAI.71.9.5210-5218.2003
14. Immunogenicity and tolerability of a multicomponent meningococcal serogroup B (4CMenB) vaccine in healthy adolescents in Chile: a phase 2b/3 randomised, observer-blind, placebo-controlled study, The Lancet, doi:10.1016/S0140-6736(11)61713-3
15. Use of an investigational multicomponent meningococcal serogroup B vaccine (4CMenB) in a clinical trial in 3630 infants
16. Adjuvant Activity of Emulsan, a Secreted Lipopolysaccharide fromAcinetobacter calcoaceticus, doi: 10.1128/CDLI.9.6.1240-1247.2002
17. Lipopolysaccharide Vaccine Adjuvant
18. Contribution of bacterial outer membrane vesicles to innate bacterial defense, BioMed Central (open access), Andrew J Manning and Meta J Kuehn
19. Analysis of outer membrane vesicle associated proteins isolated from the plant pathogenic bacterium Xanthomonas campestris pv. campestris, BioMed Central (open access), Vishaldeep K Sidhu, Frank-Jörg Vorhölter, Karsten Niehaus, and Steven A Watt
20. Routine 4CMenB immunizations effective against meningococcal strains in infants
21. Liposomal malaria vaccine in humans: A safe and potent adjuvant strategy, PNAS, L F Fries, D M Gordon, R L Richards, J E Egan, M R Hollingdale, M Gross, C Silverman, and C R Alving