Will non-injectable COVID-Vaccines end the Pandemic?

(appeared first in German on Insideparadeplatz.ch on 16.4.2021, updated on 24.4.2021 by including Oxford/Astra Zeneca and Altimmune)

Overview

Only global vaccination will stop COVID-mutants from developing and the pandemic from perpetuating. But is difficult to see how developing countries could reach broad vaccination by injections. Heat-stable vaccines which do not have to be injected would change the game by reducing the costs and enlarge the reach to many more billions of people.

Vaxart (NASDAQ:VXRT) develops such a vaccine, but it is in a close race against seven other groups. This competition presents a high risk but at the same time the cumulated results of all these companies from animal and human experiments make an ultimate success of such an approach probable. The winners not being clear investments should probably be distributed between several available contenders.

 

Only global vaccination can stop the pandemic

The COVID-pandemic has introduced unprecedented speed and efficiency into the development of vaccines. All approved vaccines are given by injection, which may be refused by 10- 20 percent anxious people. And all need medical infrastructure and manpower as well as more or less cooling before use.

Developed countries now make rapid progress towards protection of risk groups and herd immunity. There is abundant hope and talk about comparative advantages and risks of the existing vaccines and about the rosy economic prospects for the big manufacturers.

But meanwhile it has become clear that developing countries with insufficient vaccine coverage put us all at risk by allowing emergence of new and resistant variants, which will perpetuate the pandemic. Like global warming this is a global problem and cannot be solved unless addressed globally. It is difficult to see how developing countries could meet the massive amounts of infrastructure, medical manpower and money needed for vaccination by injection.

Oral/nasal vaccines as a solution?

That's why I was thrilled to discover that Vaxart (NASDAQ:VXRT) is working on an immunising tablet against COVID. This might sound outlandish, but we know from food allergies that oral antigens trigger the immune system and moreover there is the precedent of the oral polio vaccine and a nasal flu vaccine.

If an oral vaccine is to be swallowed it has first to survive the stomach. Whatever one uses as antigen it has to be packed in a way that resists the stomachic acid and only dissolves in the small intestine: This needs special knowhow outside of immunology.

Such vaccines are often thermostable and cheap, they simplify vaccine campaigns and could give a significantly better reach at lower cost.

Vaxart is already in the clinical phase...

In summary Vaxart develops oral vaccines, one against the diarrhea-causing Norovirus and another against human papillomavirus which causes cervical cancer in women. A phase II study of their oral influenza-vaccine developed in collaboration with Janssen (subsidiary of Johnson&Johnson, NYSE:JNJ) gave better protection than an injected vaccine. If confirmed this would be a big deal.

As for their COVID-vaccine it contains two viral antigens (S- and N-protein) and is therefore potentially more effective against new variants than existing vaccines targeting only the S-protein. Their preclinical animal experiments gave good protection and a phase I clinical trial published in February resulted in cellular immunity and local mucosal production of IgA but no neutralising IgG antibodies in most subjects. This was perceived as a failure and provoked a fall in share price.

However, this does not seem justified because one in 16 survivors of COVID-infection has no detectable IgG antibodies (academic.oup.com/...), therefore antibodies do not seem to be essential for defence. Animal data also show that with low antibodies cellular immunity becomes essential (pubmed.ncbi.nlm.nih.gov/...). If this COVID-vaccine could prevent the virus from reaching the bloodstream the lack of serum antibodies would not be a disadvantage. Only further clinical trials can find out if the protective effect in animals can be reproduced in humans.

Not being sure what to think about the prospects of this company I did further research and found seven other groups working in the same field. The accumulated results of these competing companies give substantial and converging evidence that ultimate success of their approach is probable.

Altimmune

Altimmune (NASDAQGM: ALT) started in february 2021 with a Phase I clinical trial of AdCOVID, a single-dose intranasal COVID-19 vaccine candidate based on an adenovirus vector similar to Astra’s COVID-19 shot. Results are expected in the second quarter. They are already readying a production facility with Swiss LONZA in Houston.

Astra-Zeneca / Oxford 

Also Oxford University in march 2021 began a phase I clinical study with nasal application of their vector-based vaccine AZD1222 developed with Astra-Zeneca (NSDAQ: AZN). It includes 30 persons and will be finished in october 2021. 

Mymetix Corporation

The Swiss Mymetix Corporation (OTC:OTCQB:MYMX) is the third company exploring the nasal route. They share intellectual property with US giant Catalent (NYSE:CTLT) about packing antigenic material in virus-like particles for local application (so-called virosomes). Their nasal COVID-vaccine developed with Baylor College in Texas gave promising preclinical data in animal experiments. It might be of interest that they have the support of the Bill Gates foundation and of billionaire Ernesto Bertarelli.

iosBio and ImmunityBio

iosBio (formerly Stabilitech) is an UK-based private company developing oral vaccines against Zika-virus and influenza based on an adenovirus-vector platform. They were short of funds and their CEO complained in an interview that big pharma had no interest for their novel approach. That is until the San Francisco physician and multibillionaire chairman of ImmunityBio (NASDAQ:IBRX) realised last year that only with an oral vaccine was it possible to vaccinate billions in the developing world and bring the pandemic to a halt. He reached out and in partnership with IosBio they develop an oral COVID-vaccine which produced cellular immunity and antibody response in subhuman primates. Their  hAd5-COVID-19 is designed to attack not only the easily mutable spike protein of the virus, but also the more stable nucleocapsid proteins, which could give it an unique advantage against variants. They are now running a phase 1b clinical trial with two spaced vaccine doses in all possible combinations of oral administration and/or injection. The personal support Mr. Soon-Shiong will assure that they will not run out of funds.

Oravax

Oravax is a new joint venture: The Israeli Oramed (NASDAQ CM:ORMP) contributes knowhow in oral delivery of pharmaceutical agents gained with their oral Insulin preparation while Indian Premas Biotech Pvt. Ldt furnishes the vaccine whose three antigens could create immunity also to variants. The production in yeasts is cheap and easily scalable. Animal experiments resulted in production of IgA and IgG type immunoglobulins. Clinical experiments start this quarter and approval is hoped for within six months.

Protein Potential and Sanaria Inc.

Prof. Kremser, director of the institute for tropical medicine in Tübingen, Germany told the Austrian newspaper "Kurier" in a January interview that they are developing an oral vaccine OraCOV in collaboration with two privately owned Maryland-based companies: Protein Potential and Sanaria Inc. They use a modified typhoid vaccine and preclinical studies are encouraging. The hope is that local mucosal immunity will not only suppress disease but also infectivity. Prof. Kremser is also leading the clinical vaccine trials of CureVac (NASDAQ:CVAC), but from the information available it seems that this oral vaccine path is independent from CureVac.

Immunitor

Immunitor is a Vancouver-based company partnered with Key Capital corporation (OTC:OTC:KCPC) and specialising in oral immunisations against a vast variety of diseases. For COVID they use tablets with heat-inactivated virus from human plasma. A phase I trial is due to end in May.

Chances for success

As said before to stop the COVID-pandemic and new mutations there is an urgent need for heat-stable vaccines that do not have to be injected. There is precedent for oral and nasal immunisation and meanwhile several groups are working on such projects. All have other preclinical or clinical projects. Their COVID-vaccines all have favourable preclinical data in animals, and five of them are already in the clinical phase while another one is starting just now. From the cumulated preclinical and clinical results it is already clear that these noninjectable COVID-vaccines can produce cellular immunity as well as local mucosal IgA-antibodies and neutralising serum antibodies of the IgG-type. Moreover, the immunisation was protective in some animal experiments.

Taking all these data together the question seems not anymore if an oral/nasal vaccination is possible but rather when, by whom and in which form it will be realised.

If the non-injected vaccine alone would not be sufficient, one could also imagine a first injection followed by an oral booster or vice versa. This would still reduce the needed infrastructure by half. Oral vaccination could also refresh an existing immunity, or protect against new variants and it could possibly even be combined with an oral flu-vaccination.

Such vaccines would have enormous markets of billions of people and could generate billions of profits.

Risks

Vaxart and most of its competitors produce huge losses and all are in a race which could not only produce one or some winners, but certainly also losers: Some could become multibaggers while some risk loss of all invested capital. And there is just no way to tell which will be which.

Last but not least such oral vaccines could become a risk for the other big players like BioNTech (NASDAQ:BNTX), Pfizer (NYSE:PFE), Moderna (NASDAQ:MRNA), CureVac and Johnson & Johnson (NYSE: JNJ). But given the advantages and the need it would not be a surprise if some of these would start their own development of no-shot vaccines.

Conclusion

If one likes this thrilling frontier one can invest a small sum of gambling capital, which I did with Vaxart after the pullback in February. But based on further study and the above reflections I plan to add add small positions in ImmunityBio, Oramed and Mymetics. It will be intersting to follow their evolution and some of these shares are so cheap that one can consider them as options to future value.

Covid-Impfung ohne Spritze – ein offenes Rennen

(erstmals erschienen auf Insideparadeplatz am 16.4.2021)

Wer ein Vakzin zum Schlucken zustandebringt, der knackt den Jackpot. Denn in der armen Welt sind die heutigen Stoffe nicht massentauglich.

Alle zugelassenen Covid-Impfstoffe werden gespritzt, was von ängstlichen Leuten verweigert werden kann. Spritzen und Kühlkette brauchen Infrastruktur, Fachpersonal und Geld, wovon nicht in jedem Land genug vorhanden sind.

In Ländern mit ungenügender Durchimpfung entstehen resistente Virusvarianten, welche die Pandemie endlos machen können. Dieses Problem ist global, kann nur global gelöst werden, und zwar kaum mit einer Spritzimpfung.

Grosses Interesse findet deshalb neuerdings die Möglichkeit von Schluckimpfungen oder Impfungen über die Nase. Tönt utopisch, aber Nahrungsmittelallergien und Heuschnupfen beweisen, dass das Immunsystem auch dort reagiert; und es gibt den Präzedenzfall der Polio-Schluckimpfung.

Eine geschluckte Impfung muss zuerst den Magen überleben: Was auch immer man als Antigen verwendet, muss es so verpackt werden, dass ihm die Magensäure nichts anhaben kann und es sich erst im Darm auflöst. Das braucht spezielles Knowhow ausserhalb der Immunologie.

Solche Vakzine sind oft wärmestabil und billig. Sie könnten per Post verschickt und durch Laien selber angewendet werden. So erhielte man mehr Reichweite für weniger Geld.

Virosom (Bild: Mymetics)

Nun zu den einzelnen Entwicklungen und Entwicklern:

• Die Firma Vaxart (NASDAQ:VXRT) aus San Francisco entwickelt schon länger Schluckimpfungen gegen das durchfallerregende Norovirus and gegen das gebärmutterkrebserregende Papillomavirus. Zusammen mit Janssen (Tochterfirma von Johnson & Johnson) entwickelt sie eine orale Grippeimpfung, welche in einer Phase II-Studie bessere Resultate ergab als eine etablierte Spritzimpfung – bei Bestätigung durch eine Phase III-Studie wäre das eine absolute Sensation. Vaxart's Covid-Impfstoff ergab guten Schutz im Tierversuch, und eine Phase I-Studie am Menschen erzeugte zelluläre Immunität und lokale Ig-A Antikörper, jedoch keine IgG-Antikörper im Serum, was zu einem Kurssturz führte. Das scheint ungerechtfertigt, weil auch einer von sechzehn Covid-Geheilten keine Serumantikörper aufweist, und weil Tierversuche zeigten, dass bei niedrigen Antikörpern die zelluläre Immunität schützt. Und wenn diese Impfung das Virus am Erreichen des Blutstroms hinderte, wäre das Fehlen von Serumantikörpern kein Nachteil. Nur der klinische Versuch kann das klären.
• Die private englische iosBio (früher Stabilitech) entwickelte Schluckimpfungen gegen das Zika-Virus und die Influenza unter Zuhilfenahme eines Adenovirus-Vektors. Zusammen mit ImmunityBio (NASDAQ:IBRX) aus Los Angeles arbeitet sie an einem oralen Covid-Impfstoff, der im Affenversuch zelluläre Immunität und Antikörper produzierte. Es läuft jetzt eine Phase 1 Studie, in der zwei Impfdosen hintereinander verimpft werden, und zwar in allen denkbaren Kombinationen von gespritzt und geschluckt. Die persönliche Unterstützung des Chefs von ImmunityBio, Patrick Soon-Shiong, einem Arzt und Multimilliardär, wird dafür sorgen, dass ihnen die Mittel nicht ausgehen.
• Die schweizerische Mymetix Corporation(OTC:MYMX) verfolgt die Route über die Nase. Mit der US-Grossfirma Catalent (NYSE:CTLT) teilt sie intellektuelles Eigentum darüber, wie man antigenes Material in virusartige Partikel packt (sogenannte Virosomen). Der nasale Impfstoff wird mit dem Baylor College von Texas entwickelt und ergab vielversprechende Resultate im Tierversuch.
• Neu im Rennen ist Oravax, ein Joint-venture. Oramed (NASDAQ CM:ORMP) aus Israel steuert das Know-how in der oralen Anwendung von Medikamenten bei, und die indische Premas Biotech Pvt. Ldt liefert den Impfstoff, dessen drei Antigene auch gegen Virusvarianten aktiv sein sollten. Die Produktion in Hefezellkulturen ist billig und in Grossmengen möglich. Klinische Versuche starten in diesem Quartal, Zulassung erhofft man innert sechs Monaten.
• Professor Kremser, Direktor des Instituts für Tropenmedizin Tübingen, berichtete dem österreichischen „Kurier“ im Januar, dass er eine Schluckimpfung OraCOV gegen Covid entwickle, zusammen mit den zwei privaten US-Firmen Protein Potential und Sanaria Inc. Verwendet wird ein modifizierter Typhusimpfstoff, Tierversuche seien ermutigend. Professor Kremser leitet auch die klinischen Versuche von Curevac (NASDAQ:CVAC), aber diese Entwicklung scheint mit Curevac nichts zu tun zu haben. 
• Weniger in Erfahrung zu bringen ist über Immunitor, eine Firma aus Vancouver in Kanada, welche Schluckimpfungen gegen eine Vielzahl von Krankheiten entwickelt. Gegen Covid verwenden sie Tabletten mit hitzeinaktivierten Viren aus menschlichem Blutplasma. Ein Phase-1 Versuch am Menschen soll im Mai beendet werden.

Wenn man all diese Daten anschaut, ist eigentlich nicht mehr die Frage, ob eine Impfung ohne Spritzen möglich wird, sondern eher wann und wie. Denkbar wäre die Anwendung geschluckt oder durch Nase allein, oder als zweite Impfung nach Spritzimpfung, oder auch als spätere Auffrischung, beziehungsweise Nachimpfung gegen Varianten.

Die meisten der erwähnten Unternehmen produzieren hohe Verluste. Und wie bei den mRNA-Vakzinen könnte das Rennen vielleicht nicht nur einen, sondern zwei oder drei Gewinner hervorbringen.

Aber sicher auch Verlierer. Auf der Verliererseite könnten plötzlich die Firmen stehen, die jetzt mit der Spritzimpfung Milliarden scheffeln, nur würde es nicht überraschen, wenn auch diese im Geheimen bereits an Schluckimpfungen arbeiten würden.

Börsenempfehlungen kann man nicht wirklich abgeben. Ich hätte lediglich offenzulegen, dass ich schon seit einiger Zeit einige Aktien von Curevac und Vaxart halte.