The science is beyond me, not the business side. I understand that side quite well, and I'd do exactly what they did, even without a guarantee of success.
NovaVax LEASED a facility. LEases can be broken as necessary. NVAX has to be proactive in preparing for vaccine production assuming a successful PIII trial. They have to assume it will be successful, otherwise they admit defeat. There are still many things that can go wrong in getting a vaccine with a successful PIII trial to market. Fortunately Novavax appears to be identifying potential roadblocks and clearing them one by one. They are hiring the 'right' people, securing facilities and educating the healthcare profession. All good signs, but far from guaranteed.
The following is a patent application for adjuvant from Novavax AB.
Hard to say what the full import is , but various things mentioned are:
-mixing adjuvants to reduce negative side effects
-RSV (both human and animal; calf RSV seems to be a large economic issue)
This all may be down the road stuff, but some may find it interesting.
QUIL A FRACTION WITH LOW TOXICITY AND USE THEREOF
Document Type and Number:
United States Patent Application 20160184427
Fraction A of Quil A can be used together with at least one other adjuvant for the preparation of an adjuvant composition, where the included adjuvant components act synergistically to enhance level of immune response and have synergistic immunomodulating activity on the co-administered antigens or immunogens. Other adjuvants can comprise saponins, naturally occurring, synthetic or semisynthetic saponin molecules; e.g. saponins and saponin fractions from Quil A, cell wall skeleton, block polymers, TDM, lipopeptides, LPS and LPS-derivatives, Lipid A from different bacterial species and derivatives thereof, e.g., monophosphoryl lipid A, CpG variants, CT and LT or fractions thereof.
Inventors: Morein, Bror (Uppsala, SE), Lövgren Bengtsson, Karin (Uppsala, SE)
Ekström, Jill (Uppsala, SE), Ranlund, Katarina (Uppsala, SE), Hu, Kefei (Uppsala, SE)
Application Number: 15/054801
Publication Date: 06/30/2016
Filing Date: 02/26/2016
1. Use of fraction A of Quil A together with at least one other adjuvant for the preparation of an adjuvant composition with synergistic effect including enhancement of immune responses and immunomodulating activity.
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of application Ser. No. 14/714,664, filed May 18, 2015, which is a continuation of application Ser. No. 14/445,690, filed Jul. 29, 2014, now abandoned, which is a continuation of application Ser. No. 10/562,866, filed May 16, 2006, now U.S. Pat. No. 8,821,881, which is a national stage application of International Appl. PCT/SE04/01038, filed Jul. 7, 2004 and which claims priority of Swedish patent Appl. No. 0301998-1, filed Jul. 7, 2003, all of which are hereby incorporated by reference.
FIELD OF INVENTION
The present invention relates to the use of fraction A of Quil A together with at least one other adjuvant for the preparation of an adjuvant composition with synergistic effects including level of immune responses and immunomodulating activity.
There is a great need for efficient adjuvant and vaccine delivery systems both for man and animal to be used for immune prophylactics or for immune therapy. For animal vaccines there are a number of different adjuvants including iscom and iscom matrix adjuvanted vaccines. However, only aluminium hydroxide and calcium phosphate adjuvants are commercially available in human vaccines, and an oil emulsion adjuvant (MF59) has recently been registered for a human influenza vaccine. Thus, there is a lack of efficient adjuvants, particularly for human vaccines. Adjuvants are not only important for enhancing the level immune response but even more for the quality or type of immune response, which has to match the type of infection the vaccine is intended to protect against. With regard to pathogens establishing themselves intracellularly like viruses, but also some bacteria and parasites, a so-called Th1 type of immune response is required for optimal immune protection, and in many cases a Th1 type of response is a prerequisite for immune protection. However, it is also now well established, that a pure Th1 or Th2 type of response may cause side effects, since a balance between the two types of the T helper cells are required for immune regulation. I.e. the Th1 response regulate the Th2 response e.g. by the production of IFN-γand the Th1 response is regulated by the Th2 response e.g. by the production of the cytokine IL10. Thus, the Th1-Th2 balance is essential to avoid side effects. To be able to induce correct type of immune response for protection against the various pathogens a number of adjuvants will be required. A Th1 response is reflected by the IgG2a antibody response, and therefore used as a marker for Th1 t helper cell response. One important aspect for adjuvants is the safety including the fact that the immune response evoked shall have a quality to avoid side effects when a subsequent infection occurs after the vaccination. Severe side effects were the case with respiratory syncytial virus when an aluminium hydroxide adjuvanted formalin inactivated respiratory syncytial virus (RSV) vaccine was tried in children nearly 30 years ago. The vaccinated children became sicker and there was a higher death rate among them after natural infection with RSV than in non-vaccinated children.
Acute toxicity or side effects have been major concerns for both veterinary and particularly human use of quillaja saponins in vaccine preparations. Theses goals were only partially met with success, the purified fractions e.g., QA-21 (EP 0 362 279 B2) and combinations of fractions A and C (WO 96/11711, lscotec-patent) were indeed chemically defined compared to “Quillaja Saponaria Molina” but they still caused some toxicity and side effects.
It has now turned out that fraction A of Quil A has a low toxicity, and in low dose enhance and the level of immune responses and the immunomodulatory capacity of other adjuvants in suboptimal doses, which when used by themselves may be toxic or cause side-effects in efficient doses. Thus, it facilitates the use of other adjuvants which, when used by themselves, might be toxic in doses they are efficient.
SUMMARY OF THE INVENTION
The present invention relates to the use of fraction A of Quil A together with at least one other adjuvant for the preparation of an adjuvant composition with synergistic effect to enhance the level of immune responses and immunomodulating activity. It especially concerns the use of fraction A of Quil A in a composition comprising iscom particles wherein the different fractions of Quil A are integrated into different iscom and iscom matrix particles.
DETAILED DESCRIPTION OF THE INVENTION
The invention relates to the use of fraction A of Quil A together with at least one other adjuvant for the preparation of an adjuvant composition with synergistic effect to enhance the level and quality immunomodulating activity. It especially relates to the use of fraction A of Quil A together with one or more other adjuvants where fraction A at a low and well tolerated dose synergistically enhance the immuno enhancing effect of the co administered adjuvant, which by its own is too toxic for prophylactic or clinical use. I.e. a low well tolerated (otherwise sub-optimal) dose of the co-administered adjuvant is rendered efficient and feasible for use. Thus, the other adjuvants are preferably those, which have a substantial toxicity and the dose of which has to be lowered to be accepted for prophylactic and clinical use, but also adjuvants which are weak and cannot by their own enhance efficient levels of immune responses or exert efficient qualitative immunomodulating capacity......
In a preferred formulation iscoms and iscom matrix have been formulated with fraction A and C of Quillaja in different iscom particles, which cause minimal side effects (see the examples). These iscoms have been compared with a formulation comprising 70% of fraction A and 30% of fraction. C of Quil A called 703 and produced according to WO 96/11711, which is in clinical trial in man for a human influenza virus vaccine. According to WO 96/11711 the A and C fractions are integrated into the same particle. The toxicity study was carried out in newborn mice, which arc much more sensitive than adult mice. The study shows that the newborn mice better tolerate the new iscoms produced from fraction A of Quil A than the 703 formulation. Furthermore, the efficacy of the new formulations according to the invention is tested with antigens from a pathogen i.e. human respiratory syncytial virus hRSV and with a weak antigen i.e. ovalbumin (OVA). A synergistic effect of fraction A of Quil A in a matrix formulation named QWT is shown in example 1. Also strong antigens like cholera toxin (CT) and tetanus toxin can be modulated by the adjuvant formulations according to the present invention by enhancing antibody increase, but above all by potent immuno modulation as described............
Respiratory syncytial virus (RSV) is a major pathogen for young children (hRSV) but also for elderly. A closely related virus (bRSV) is a pathogen for young calves causing severe disease and high economical losses for calf breeders. The envelope proteins of hRSV were selected as model antigens, because they represent antigens from a pathogen for which a vaccine is lacking and for which there is a great need. The newborn mouse represents a model for the newborn, and a very sensitive animal, which requires a vaccine formulation virtually free of side effects, and a model in which important immunological reactions can be measured because of available reagents techniques. An early vaccine against hRSV was tested in children, but it did not protect against disease. On the contrary it exacerbated disease when a subsequent natural infection occurred. In this experiment we have selected 703 as a quillaja component in the ISCOM to compare with the present invention, because a 703 vaccine formulation is in human trials, thus a candidate for human vaccines. In the present experiment the toxicity of QWT iscoms and 703 iscoms is compared.......
Doses of 0.66 and 1 μg killed 65 resp. 50% oldie mice injected with the 703 iscoms, while all the mice injected with the QWT iscoms survived including those receiving 1 μg of QWT iscoms.
The QWT iscom is well tolerated even by a harsh route as the i.p. route in a very sensitive animal model. It is better tolerated than a formulation being in human trials.
In this example the serum antibody response was tested with the envelope proteins G and F of hRSV as a model for vaccine antigen. The hRSV antigens were selected because hRSV represents antigens from a pathogen for which a vaccine is lacking and for which there is a great need. The newborn mouse represents a model for the newborns, which are immunologically immature requiring an adjuvant system with potent immune modulatory capacity (WO97/30727). Furthermore, a newborn mouse represents an animal system, which is very sensitive and requires a vaccine formulation virtually free of side effects. Similar vaccine formulations were tested as described in example 2, i.e. the QWT AND 703 iscoms......
The results are illustrated in FIG. 4. After one immunisation both adults and newborns responded with RSV specific IgG1 antibodies measured by ELISA. After one immunisation the QWT iscoms induced higher RSV specific IgG1 antibody response in the newborn than the 703 iscom. Otherwise, there were no clear differences between the two iscom formulations as regards to their capacity to induce IgG1 and IgG2a RSV specific antibody responses in adults or in newborns. The antibody titres in general were 10-fold higher in the adults than in newborns. The IgG2a response to RSV was insignificant after one immunisation in newborns regardless they were immunised with QWT or 703 iscoms. RSV specific IgG2a were clearly detected after one immunisation in adults.
The serum antibody responses were at least as high after 1 as well as after 2 immunisations of newborns or adults with the QWT iscom formulation as after the same immunisation schedules with the 703 iscom. In view of the results of example 2, showing that the QWT iscom has a considerably lower toxicity than the 703 iscom, the QWT iscom is preferred for vaccine formulation.....
Cytotoxic T lymphocytes (CTL) are essential for the immune defence against intracellular pathogens. Above all virus-infected cells are targets for CTL by killing the infected cells. Consequently, CTL is an important arm of the immune defence against viral infections. This example shows that QWT iscoms containing hRSV envelope antigens specifically induce and efficiently prime for memory CTL both in newborn and adult mice. It is surprising, that the QWT iscoms induced CTL memory as efficiently in the newborns as in adults in view of their immature immune system.......
Already 1 week after priming of newborn and adult mice with QWT iscoms their splenocytes generated to restimulation in vitro with hRSV infected fibroblasts (BCH4) strong cytotoxic T cell response (FIG. 5). No lysis was observed against uninfected target cells (BC in FIG. 5).
RSV-QWT iscoms induce strong cytotoxic T cell responses in 1-week-old mice and in adult mice. Strong specific cytotoxicity is observed already 1 week after one immunisation. In view of the strong adjuvant effect of QWT iscoms and its low toxicity, this vaccine delivery and adjuvant system is very likely to be valuable for both human and animal vaccines.
I fully agree this board is quality, and beyond me from a scientific standpoint. However, putting a guarantee on *anything* in trial phase shows that the business/risk part of this is far beyond you, as well. There simply are no guarantees, and the company making forward plans is simply pertinent business, but in no way a guarantee of success. The science itself is far more of an indicator than any employee postings.
Prove to us why it isn't a guarantee.
I have never seen you here before, ever, or any part of the lengthy discussions we have had regarding the science for PII and PIII. And until you can prove yourself, by talking about the science and all the factors used in weighing risk vs. success, everyone will disregard you here. No offense but this board is quality that is beyond you based on what you've written so far.
At least you are long so you got that going for you.
I think that's a reasonable point, but having worked with gov agencies on things with this, promises made for grants and things as such fall through all of the time.
If they had covered anytime between January 7 and today, they would have made a lot more money (or lost less). What SP did they go short at?
Hey Wily and nutmeg...thanks for the discussion and delineation. It's fun to watch this kind of exchange as it hones in on the science in a way most of us can understand. Great of you to share your thoughts.
except shorts who get sane and jump off the train now, cover and buy. watch the covering action into the close.
agree... but promotion depends on what audience one is seeking... medical... general public... investors... The FDA and ACIP acceptance offers a huge amount of confidence... especially when appearing in NEJM and various publications (AARP) of all sorts... plus TV... I want to see 60 minutes do a segment on the technology itself... A good PR agency should handle these matters... they know how.
At this time you risk not being in, and having to chase it on the way up if a catalyst occurs.
I wouldn't see this slow rise taking much of a pause. I'm sure there will be a down day here or there but I'd be willing to bet on 8/10 green days.
Just my opinion.
Thinking about taking some profits and buying back in next week. Opinions?
The company's guarantee to the local community to hire 850 people speaks volumes to management's confidence and to the way forward. Nothing misleading about that IMO.
Sentiment: Strong Buy
Look, I am a perma-long...but what you're saying just isn't true. They are hiring employees to PREPARE for being successful, but it is far from a guarantee. We shouldn't mislead people in such a manner, it's disingenuous.