التكنولوجيا الحيوية

الجيل التالي من اللقاحات

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قوة اللقاحات

Since their invention in the 19th century, vaccines have been a massive healthcare revolution. In part, they drastically reduced mortality from deadly diseases, with no less 154 مليون حياة تم إنقاذها خلال الخمسين عاماً الماضية، وفقاً لمنظمة الصحة العالمية (WHO).

Vaccines have also entirely eradicated the terrible disease that was smallpox, والذي يُقدّر أنه أودى بحياة 500 مليون شخص خلال المائة عام الأخيرة من وجوده.

The next on the chopping block might be polio, with the last pockets of endemic polio in Pakistan and Afghanistan. Polio used to kill half a million people every year before vaccination.

المصدر: المصدر: Delaware Journal Of Public Health

And, of course, the recent pandemic has seen vaccine and anti-vaccine movements at the forefront of the public discourse, with mRNA vaccine technology making a spectacular entry into the market and public awareness.

Despite these successes, infectious diseases still account for around 40% of all recorded deaths in the world. In part, this is due to insufficient vaccination coverage in poor developing countries, but it is also due to some diseases still resisting the effort to develop vaccines against them.

This might change thanks to many new technologies converging into creating a new generation of vaccines.

المصدر: Phrma

كيف تعمل اللقاحات

The base principle of a vaccine is to “train” the immune system before it encounters a dangerous disease caused by a virus or bacteria (the pathogen).

This works by presenting to the body either part of the pathogenic (“disease-causing”) bacteria or virus (the antigen) or the full pathogen, which is either killed or weakened so it cannot cause the disease.

When it is done, the body’s immune system starts developing proteins called antibodies. These antibodies “click” to specific parts of the pathogen or antigen, recognizing it in the same way a key and lock work.

المصدر: Cusabio

It is the specificity of the antigen-antibody interaction that allows for the antibody to neutralize the pathogen and protect the person against the disease.

You can also watch this 3min video animating these base principles of vaccination:

For some diseases, like smallpox, this worked so well that we managed to fully exterminate the disease.

But others are trickier. Here are some of the methods pathogens can use to escape vaccines and the immune system:

  • المستضدات عالية التغير.This is the strategy used by the flu and common cold viruses, with so many variants that every year, the seasonal flu is a “new” disease from a vaccine and immune system point of view.
  • انخفاض التركيز والاختفاء. Some diseases are very good at hiding away from the immune system. They usually cause chronic diseases, but if the immune system cannot find them, vaccination is less useful or might not work at all.
  • تحييد جهاز المناعة. Most notably, this is how HIV works, directly attacking the antibody-producing systems of the body.
  • الهجوم السريع. Some diseases strike so quickly that the body does not have the time to react and produce enough antibodies in time. This is notably a problem with very aggressive & deadly diseases like Ebola.

الأهداف التالية للتطعيم

العدوى المزمنة

As mentioned above, a segment of diseases that have overall resisted efforts to develop vaccines are chronic diseases.

Because these diseases evolved to create an infection that stays below a threshold that would trigger an efficient immune response, it is hard to create a vaccine that works. This includes a few major global killers.

الملاريا

There were 249 million cases of malaria in 2022, causing around 600,000 deaths per year, with most of them children under 5 years old. This is also a very debilitating disease, leading to missed school and work days, loss of energy, income, and economic opportunities, altogether a cause of and made worse by poor economic conditions.

For example, in Mozambique, كانت الملاريا سبباً في 45٪ من الاستشارات الخارجية و24٪ من دخول المستشفيات في عام 2015.

“تكلفة الأسرة المتوسطة المرتبطة بالملاريا غير المعقدة تمثل ما بين 10٪ (US$ 1.63) و21٪ (US$ 3.46) من الإنفاق الشهري لعائلة في زامبيزا، بينما تكلفة الحالة الشديدة (US$ 64.90 وUS$ 81.08) تتجاوز متوسط الإنفاق الشهري للفرد بأكثر من ثلاثة أضعاف.”

Malaria Journal

Malaria is caused by a parasite that hides in the patient’s liver and is transmitted through mosquito bites. It also has more than 60 جينًا متغيرًا للمستضد ويتنقل بينها ليختبئ أكثر عن جهاز المناعة.

Until recently, a malaria vaccine has been difficult to develop, leading to the main effort to control the diseases focused on targeting the mosquitoes instead. Drugs are also a possibility, but the parasite tends to develop resistance against previously efficient molecules.

اللقاحات المتاحة حالياً

In 2021, the WHO recommended for widespread use of the RTS, a malaria vaccine for children in affected areas, produced by pharmaceutical giant GSK. In 2023, لقاح ملاريا ثانٍ (R21/Matrix-M)، تم تطويره من قبل جامعة أكسفورد, was approved.

Both approved malaria vaccines do not fully avoid the disease, but radically reduce the severity of the symptoms and the risk of death. These vaccines use artificial proteins and virus-like particles.

Among the candidates for new, more efficient vaccines are the PfSPZ vaccine in development by Sanaria. It is now in Phase 2 of clinical trials and uses a genetically modified version of the whole parasite.

“فقط لقاحات Sanaria من نوع P. falciparum sporozoite حققت >90٪ فعالية لقاح ضد العدوى البشرية المُتحكم فيها للملاريا”

Sanaria

 الإيدز/فيروس نقص المناعة البشرية

HIV, the virus causing AIDS, كان يصيب 39 مليون شخص في عام 2022، مما أدى إلى 630,000 وفاة. While patients can see lower mortality and higher quality of life by using anti-HIV drugs, a cure and eradication of the disease will likely require a vaccine.

By attacking the CD4 cells, a part of the immune system, the virus manages to avoid detection until it is too late.

A vaccine has been very difficult to develop, and it is still unclear what will work.

Among the notable efforts and potential cures in development are:

أخرى

It would be too long to cover all the existing vaccine initiatives. You can read more about it in this 11-page report.

Among the other important diseases with active efforts made to develop a vaccine against them are:

  • حمّى الضنك
  • دودة الخطاف
  • الليشمانيا
  • الفيروس المضخم للخلايا (الهربس)
  • مرض لايم
  • القوباء الحزامية

العدوى العدوانية

New diseases and aggressive patterns of infection can overwhelm the immune system and lead to very high death rates in infected patients.

One example is Ebola and other hemorrhagic fevers, with death rates in the 30-50%. There are currently 2 Ebola vaccines, Merck’s Ervebo approved in 2019, and Johnson & Johnson’s (JNJ ) Zabdeno+Mvabea.

Of course, another example is coronavirus, the cause of the COVID-19 pandemic, but also of the previous deadly outbreaks of متلازمة الشرق الأوسط التنفسية (MERS-CoV) and 2002-2004 متلازمة الالتهاب الرئوي الحاد الشديدة (SARS) 2002-2004.

تقنية اللقاحات الجديدة

Previous generations of vaccines were based on a few techniques, like using a weakened part of the virus/bacteria, a dead full-version of it, just fragments, or more recently the antigen expressed into another vector through genetic modification.

Modern biosciences are now coming with many new potential modes of vaccination.

لقاحات mRNA

Widely promoted and very quickly adopted because of the COVID-19 pandemic, mRNA vaccines have a powerful advantage over traditional vaccines.

Instead of slowly finding how to safely inactivate a virus, or how to efficiently modify another vector, it can directly “program” a cure in just 3-4 weeks. This is because the mRNA code can be directly written once the targeted virus genome is known, something that was achieved in the very first week of Covid-19 identification.

Other COVID vaccines existed during the pandemic, but the quick development cycle of mRNA vaccines made it the perfect solution for a novel disease.

More mRNA vaccines are now in development, especially by the 2 companies that benefited the most from the mRNA vaccines’ sales during the pandemic.

لقاحات الحمض النووي

While technically, mRNA vaccines are a sub-category of nucleic acid vaccines, the technology is broader and includes a few other potential types of vaccines.

The first one is DNA vaccines, which use a molecule of DNA instead of RNA. Over 160 different DNA vaccines are currently being tested in human clinical trials in the United States. يُقدّر أن 62٪ من هذه التجارب مخصصة للقاحات السرطانية و33٪ موجهة للقاحات ضد فيروس نقص المناعة البشرية (HIV).

زراعة اللقاحات في المزارع

We are used to thinking of vaccines as full or parts of a virus/bacteria. Even antigen-based vaccines are produced by multiplying this antigen in unicellular organisms.

But this might change with the progress of genetic modification, with the hope to one day produce vaccine material the way we grow food.

Plant-based vaccines could be growing the vaccine component in open fields or greenhouses. This would radically reduce production costs.

The issue is that most antigens will not be produced in plants the way they would in bacteria or viruses, due to different cellular biochemistry, notably the sugars added to proteins.

A more promising field than growing vaccines in plants like corn or wheat is using microalgae. The technology is now starting to be used for animal vaccines, and جدار خلية الطحالب الدقيقة يوفر “كبسولة” مسبقة تجعل اللقاح قابلاً للأكل بدلاً من الحاجة إلى تنقيته وحقنه

جسيمات عضوية

Changing the fundamental technology of vaccine production is not the only way to improve vaccines.

For example, most vaccines use “adjuvants,” chemical compounds that boost the immune system. However, these can cause unwanted side effects as they stimulate ALL immune reactions, not just the ones intended by the vaccine.

Instead, a recent publication by a research team from MIT might have found a solution to increase vaccine effectiveness by using a novel type of adjuvant leveraging nanotechnology.

They used a metal-organic framework (MOF) nanoparticle, which acts as an adjuvant, boosting a specific immune reaction instead of a generalized reaction like with classical adjuvants. We discussed this discovery in more detail in our article “تعزيز فعالية اللقاح عبر جزيئات نانوية معدنية عضوية”

لقاح الإنفلونزا المختلط

A more powerful or quicker development cycle might still leave highly variable viruses like the seasonal flu free from a perfectly efficient vaccine.

This is because these vaccines target antigens that are highly variable, allowing the virus to quickly escape the acquired immunity.

Researchers are now finding that they can force the immune system to focus on other, less variable sections of the virus. We discussed how this was done by combining 80,000 mutated versions of the flu virus in our article “لقاحات الإنفلونزا يمكن أن تُطلق في الظلام – العلماء يبحثون عن إضاءة نهج جديد”.

تحسين اللوجستيات والتوصيل

Other improvements that could be made regarding vaccines are related to logistics and methods of administration. A lot of vaccination campaigns come from logistics, cold storage, the need for medical professionals to inject the vaccine, etc.

For example, باحثو كامبريدج وجدوا طريقة لحجز الجسيمات الفيروسية في طبقة رقيقة جداً من زجاج السكر، مما يسمح بالتخزين في درجات حرارة تصل إلى 113°F لمدة ستة أشهر.

As discussed above, an algae-based vaccine could be delivered orally, like a vitamin pill.

Another option could be رقع الميكرو-مصفوفة اللقاح (vaccine-MAPs), also known as microneedle patches. This injection-free option is painless and could improve both logistic challenges and compliance while making the administration of vaccines quicker.

السجلات الرقمية للقاحات

Lastly, technology could help monitor the vaccination status of individual people and the whole population. Digital records can help decision-makers design better vaccination campaigns, anticipate epidemics, and improve vaccination rates.

لقاحات الأمراض غير القابلة للانتقال

While probably not technically “vaccines,” there are many new vaccine-like treatments in development looking to prevent death by modifying the body’s chemistry or immune system.

لقاحات السرطان

As cancer is quickly becoming a larger cause of death than infectious disease worldwide, better treatments are becoming increasingly important.

Technically, some cancer vaccines already exist for cancers induced by infectious diseases, like HPV and Hepatitis B.

Another category is therapeutic cancer vaccines. They are looking to make the immune system react to cancer cells the way it would to an infectious pathogen.

This is done by inducing the immune reaction against antigens present in the cancer cells.

Already, several cancer vaccines have been approved for سرطان البروستاتا والمثانة، بالإضافة إلى الميلانوما.

المزيد قيد التطوير تقريباً لكل نوع من أنواع السرطان, especially the ones resistant to currently available therapies, like pancreas cancer.

لقاحات مكافحة الشيخوخة

One possibility to fight aging is creating induced-Pluripotent Stem (iPS) cells, with massive potential to repair and rejuvenate the body’s tissues. This reprogramming could be achieved through a transient genetic reprogramming, relying on an mRNA-based method.

This method is very similar to the mRNA vaccines, except the target is not to create immunity but to temporarily modify the targeted cell.

We look at transient cellular reprogramming and other anti-aging potential technologies in our article “الشيخوخة جزء من الحياة – وهذا لا يعني أننا لا نستطيع القتال”.

لقاح الزهايمر

With the population aging, Alzheimer’s is a growing public health concern.

The American company Vaxxinity reported successful phase 2 trials of UB-311, targeting toxic amyloid beta forms in the brain, which not only triggered an immune response but also demonstrated safety.

العديد من لقاحات الزهايمر المحتملة الأخرى, with others targeting the amyloid proteins, as well as targeting the tau protein, or inflammation.

السكري

Type-1 diabetes is an autoimmune disease where the body’s immune system targets the insulin-making cells in the pancreas. So it makes sense that a “vaccine” modulating immunity could potentially prevent this disease.

تمت الموافقة على TZIELD من شركة Macrogenics في عام 2022 and reduces the risk of developing type-1 diabetes. While not foolproof, this is a massive step into one day fully avoiding the disease developing or reversing the damages it causes.

لقاحات الالتهاب

A vaccine targeting السيتوكينات البشرية، وهو عامل رئيسي في الربو، في عام 2023. لقاحات أخرى (في الواقع أجسام مضادة أحادية النسيلة) تستهدف الصدفية are also in development.

Similar progress in managing inflammation and autoimmune disorders is ongoing, with many vaccine candidates targeting cytokines as well, which include:

شركات اللقاحات

1. BioNTech (BTNX)

BioNTech (BNTX ) is doubling down on the technology that forms the core of its business. The company behind the Covid mRNA vaccine sold by Pfizer (PFE ) is now using the money made during the pandemic to widely expand its offer.

It is now developing mRNA vaccines for shingles, tuberculosis, malaria, HIV, and the herpes virus. This makes it a leading company in the field of mRNA vaccines, with only its competitor Moderna (MRNA) developing more mRNA vaccines than BioNTech.

BioNTech is also exploring the potential of mRNA for cancer, with  12 different candidate products for cancer treatment in its pipeline.

المصدر: BioNTech

Finally, it also has in its R&D pipeline some cell therapies and other non-mRNA potential cancer treatments.

mRNA has been a revolution in therapy for viral infection. BioNTech is counting on mRNA being an equally massive revolution in oncology.

With a presence in the whole spectrum of mRNA vaccine potential, both for infectious diseases and for cancer, BioNTech provides investors with exposure to both.

2. Immatics

IMTX مخطط السعر

Immatics is looking to reprogram the immune system to target cancer cells, making it a leader in cancer “vaccines”, المعروفة أيضاً بعلاجات TCR.

خطوتان أساسيتان مطلوبة:

  • اختيار هدف سرطاني حقيقي يُعبّر عنه طبيعياً وبشكل محدد بمستويات ملحوظة على الورم.
  • تطوير مستقبل TCR المناسب والقوي الذي يتعرف بدقة على هدف السرطان المختار مع حد أدنى أو عدم وجود تفاعل متقاطع مع الأنسجة السليمة.

المصدر: Immatics

The company’s R&D pipeline is split between therapies where the cells are collected for each patient (autologous) and “off-the-shelf” therapies (heterologous).

The company has established a strong line-up of partnerships, including with BMS, Moderna, and Editas.

المصدر: Immatics

The partnership with Moderna for a “strategic multi-platform collaboration” تم تأسيس الشراكة في نهاية عام 2023.

Immatics’ products are still at an early stage but have massive potential, something clearly recognized by leaders of the industry like BMS and Moderna.

The company’s candidate therapies target melanoma and cancer in the ovaries, lungs, uterus, bladder, head & neck, as well as other types of solid cancers.

الخلاصة

Vaccination has changed the world, saving hundreds of millions of lives. And it might soon have an equally large impact, potentially wiping out deadly diseases that have plagued humankind for eons.

We might also see relatively soon the emergence of new vaccine types. Some will leverage new technologies to target diseases so far not targeted by vaccines. Or to make vaccines that would be injection-free, painless, edible, cheaper, and that could be stored at room temperature.

Finally, our deepening understanding of the immune system and the mechanics of inflammation might open the way to “quasi-vaccines” preventing or curing diseases as varied as Alzheimer’s, asthma, or diabetes.

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جوناثان هو باحث كيميائي حيوي سابق عمل في تحليل الجينات والتجارب السريرية. وهو الآن محلل أسهم وكاتب مالي يركز على الابتكار ودورات السوق والجيوسياسة في منشورته 'The Eurasian Century".