New Meningitis B Vaccine Uses New Adjuvant Not Proven Safe

Novartis has scored big with approval of its meningitis B vaccine. But what dangers lurk? Should you be suspicious when an adjuvant is disguised as an antigen?

by Heidi Stevenson

A new vaccine by Novartis, Bexsero, has just been approved by the FDA and is already headed for vaccine schedules in the US and UK, planned for children as young as two months. Bexsero contains new adjuvants that may carry dangers equivalent to Freund’s adjuvant, which is used to create autoimmune disorders in lab animals.

The new adjuvant, called OMV Por A, is not being named as an adjuvant by Novartis. It is, instead, referred to as an antigen, as documented in a combination press release/advertisement by Norvartis¹. Why? Why would Novartis label an ingredient as an antigen—when its function is demonstrably as an adjuvant? Could they be hiding something?

Outer Membrane Vesicles

OMV stands for outer membrane vesicles. They are substances contained in protrusions created by various bacteria to help them exist in threatening environments, which is a significant portion of an infectious agent’s life cycle. Unsurprisingly, they tend to be recognized by invaded systems. As a result, they are known to cause systemic inflammatory responses^2,3.

This is, in fact, why OMVs have been targeted as potential adjuvants. When proposed antigens alone cannot exact much of a response when injected, an adjuvant is used to force the immune system to become hyperactive. The problem has been that adjuvants, by their nature, are toxic. It’s their toxicity that causes the heightened inflammatory response that results in antibody production.

In the case of Novartis’ Bexsero vaccine, the OMVs come from the same bacterium as the vaccine’s antigens, Neisseria meningitidis. They have been well studied for use as an adjuvant. Nonetheless, Novartis has consistently named the OMV portion of its vaccine as an antigen, including in a briefing to the FDA⁴. In this briefing, they make clear that the OMV portion does not stand alone, but:

The fHbp and NHBA fusion proteins, and NadA drug substances were formulated with OMVs derived from New Zealand strain NZ98/254 (OMV NZ) and then adsorbed to aluminum hydroxide as an adjuvant.

That is, the OMV part of the vaccine is not intended to act as an antigen by itself, but is used to create reactivity to the New Zealand strain in the fusion proteins fHbp and NHBA.

Novartis Study

A study published 8 February of this year and funded by Novartis⁵ found that Bexsero (referred to as 4CMenB prior to approval) had its best effect when OMVs were included, in spite of the fact that it treated OMVs as equivalent to the other antigens:

4CMenB immunogenicity in this study is consistent with previous small trials that found 4CMenB to be more broadly immunogenic when given with OMVs, possibly because of a synergistic or enhancing effect of the OMV.

Thus, though Novartis refers to the OMV it uses as an antigen, it functions as an adjuvant. It enhances the effects of the real antigens.

Immunoglobulin G (IgG) is a part of the immune system that normally exists and is unrelated to specific disease antibodies. IgG is not specific to a particular pathogen, but can react to many. The Novartis study⁵ pointed out that concentrations of IgG were increased with the addition of OMV.

In determining adverse events, the Novartis study followed the subjects for only 6 months—and they used “a study investigator’s judgment based on temporal relationship and biological plausibility criteria”  to decide whether reported adverse events actually should be counted.

The study used people who were getting other vaccines at the same time as controls. They provided limited reporting on the safety results at the six-month point, but did state that 166 serious adverse events were reported, though they determined that only 20 were related to their meningitis B vaccine or other vaccines given at the same time. I’ll leave it to the reader to determine how valid their safety claims are.

Ineffective As an Antigen, But Very Effective as an Adjuvant

An adjuvant is any substance that enhances the body’s immune response to an antigen. The biggest problem faced in vaccine development is achieving a strong enough response to a proposed antigen, especially with the new genetically engineered antigens. Aluminum, the most common adjuvant, adequate in promoting antigen development with the new genetically engineered vaccines. However, a string of studies has shown that OMVs work very well.

A paper published by PNAS states in its abstract⁶:

[P]rotein subunit vaccines are attractive for widespread immunization, but their disadvantages include poor immunogenicity and expensive manufacture. We show here that engineered Escherichia coli outer membrane vesicles (OMVs) are an easily purified vaccine-delivery system capable of greatly enhancing the immunogenicity of a low-immunogenicity protein antigen without added adjuvants.

That is a clear statement of OMVs being used to enhance the reaction to antigens. It’s true that OMVs can act as carriers of the antigens—but that’s also true of aluminum used as an adjuvant.

Another study discusses the use of OMVs from N. meningitidis, the target of the new meningitis B vaccine, as an adjuvant:

OMV of N. meningitidis was shown to be able to induce high levels of antibodies when applied as an adjuvant for T-independent antigens. In this study OMV was used as an adjuvant with group A meningococcal capsular polysaccharide.

The Annals of Microbiology brought us the report of a study that investigated the use of Neisseria meningitidis OMVs as an adjuvant for use with an antigen against brucellosis⁷. It was compared with Complete Freund’s Adjuvant and Incomplete Freund’s Adjuvant, and found to result in higher titers than either one. The study claims that the OMV adjuvant was safe, but didn’t state on what basis that determination was made.

Freund’s adjuvants have been well known for the better part of a century, but they are never used in humans because they’re so dangerous. They are routinely injected into lab animals to create autoimmune disorders that are indistinguishable from some of the worst autoimmune diseases known in humans, including multiple sclerosis and lupus erythematosus.

Adjuvant Potency

Should the fact that OMVs produced a stronger titer than Freund’s adjuvants be of concern? We aren’t, of course, provided with information by Novartis to know for certain. However, what we do know is chilling—and it certainly helps explain why the real purpose of using an OMV has been hidden.

It’s believed that adjuvants function by creating an immune system storm, by exciting the immune system so that it reacts to the intended antigen. Aluminum, which has no place in human biology, is a toxin. Its ability to create excitement in the immune system isn’t terribly surprising.

Another adjuvant, squalene, is highly effective as an adjuvant, but its adjuvant talent doesn’t come from toxicity. In fact, it’s quite the opposite. Squalene is virtually identical to a common substance in the body, cartilage. You can eat it with no trouble whatsoever. But when it’s injected, it’s seen as an invader. It’s a natural substance commonly found in the body, but injection is not a normal form of entry. It is, therefore, taken as an invader by the immune system. Therefore, antibodies against it are created. Those antibodies then search for it—and they find it everywhere in connective tissues. It’s the normalcy of squalene that makes it so dangerous upon injection.

OMVs are part of a typical expression of a bacterial invader, so it isn’t surprising that they result in a strong immune response. The question that must be asked—and clearly hasn’t been—is What will the immune system do as a result of OMV injection? We know part of the answer: Antibodies to the antigen are created. But is that the end of it?

We don’t know. What we do know is that something in the Bexsero vaccine does create a strong immune system response. It does result in more fevers and injection site inflammation. Though it appears to have been minimized, it does result in more severe adverse events. Clearly, something serious is happening. What’s happening, we don’t know. Whether it’s permanent, we don’t know.

Not knowing is not acceptable.

The 4CMenB vaccine consists of 50 μg each of fHbp1, NadA, and NHBA fusion proteins, 25 μg of detoxified OMV from N. meningitidis strain NZ98/254, 1.5 of mg aluminum hydroxide, and histidine 10mM in 0.5 mL of water for injection.

Sources:

1. Positive CHMP opinion for groundbreaking vaccine Bexsero® against devastating MenB disease
2. 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
3. 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
4. Briefing Materials for the Meeting of the Vaccines and Related Biological Products Advisory Committee, 7th April, 2011
5. 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
6. 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
7. Outer membrane vesicle of Neisseria meningitidisserogroup B as an adjuvant to induce specific antibody response against the lipopolysaccharide of Brucella abortus S99
8. Contribution of bacterial outer membrane vesicles to innate bacterial defense, doi:10.1186/1471-2180-11-258
9. Analysis of outer membrane vesicle associated proteins isolated from the plant pathogenic bacterium Xanthomonas campestris pv. campestris, doi:10.1186/1471-2180-8-87
10. PorA Variable Regions of Neisseria meningitidis, Emerging Infectious Diseases
11. Restored functional immunogenicity of purified meningococcal PorA by incorporation into liposomes
12. 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
13. 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
14. Use of an investigational multicomponent meningococcal serogroup B vaccine (4CMenB) in a clinical trial in 3630 infants
15. Adjuvant Activity of Emulsan, a Secreted Lipopolysaccharide fromAcinetobacter calcoaceticus, doi:  10.1128/CDLI.9.6.1240-1247.2002
16. Lipopolysaccharide Vaccine Adjuvant
17. Contribution of bacterial outer membrane vesicles to innate bacterial defense, BioMed Central (open access), Andrew J Manning and Meta J Kuehn
18. 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
19. Routine 4CMenB immunizations effective against meningococcal strains in infants

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