In the past 100 years, only 6 products have been approved, which is the "adjuvant" behind the vaccine competition

picture source @ Vision China

writing | Amino observation , author | Fang Taozhi

Speaking of vaccines , Almost everyone can say two sentences , But when it comes to adjuvants in vaccines , Few people know .

It's not surprising , Compared with vaccines , The development of adjuvants almost belongs to “ The primeval forest ”. from 1920 So far this year , The United States FDA Only 6 paragraph . As for domestic , Most vaccine enterprises do not have the research and development of new adjuvants 、 throughput .

Only a handful of approved products , It's not that adjuvants are not important . On the contrary , In the vaccines of some technical routes , It is indispensable . The presence of adjuvants , It can make the live attenuated vaccine of the traditional route lose the market ; But because of its addition , It can also bring the inactivated vaccine back to life . Adjuvants , It's amazing .

It's just , Because adjuvant research and development 、 Industrialization is too difficult , As a result, few new products are available .

With the explosion of covid-19 vaccine , This once unknown hero has also begun to be known by more people ; The importance of adjuvants , It has also been raised to an unprecedented height .

Today's vaccine industry has become more lively than ever , A battle about adjuvants “ Pioneer ” Contest , Also under the noise , Smoke is rising .

unknown hero , But he can change his life against the sky

By name , Adjuvant seems to be just a supporting role in vaccine . But actually , Is not the case,

In addition to live attenuated vaccines 、 The whole cell vaccine does not need adjuvant because of its adjuvant nature , Second generation vaccines such as recombinant protein vaccines , Most of them are inseparable from adjuvants .

that , What magic does adjuvant have ？

If the vaccine is compared to a bullet , Then the antigen is the warhead of the bullet , The adjuvant is the gunpowder in the bullet , Responsible for ejecting the thruster , Break through the barrier of natural immunity .

In terms of function , Adjuvants can be roughly divided into three categories .

The first category , It is an adjuvant for vaccine delivery , Add the necessary amount of vaccine antigen and immune stimulant , Presented to the immune system to induce immunity . Such as aluminum adjuvant 、MF59、AS03 Isoadjuvant .

The second category , It is an adjuvant that stimulates the immune response . Such products contain immune stimulants or enhancers , Use receptor-mediated signaling pathways to regulate immune response , Enhance the immunogenicity of antigens . For example, lipid monophosphate A( MPL)、QS21、CpG1018 etc. .

among ,CpG 1018 Adjuvant is a kind of TLR9 Agonists , It can stimulate B fine , Promote humoral immunity ; At the same time, it can also stimulate the activation of dendritic cells , And then stimulate specificity T cells 、 Produce memory cells , The combat effectiveness is significantly stronger than that of traditional aluminum adjuvants .

The third category , It is a compound adjuvant composed of the first two types of adjuvants . Such as GlaxoSmithKline AS04 and AS01 Adjuvants .

AS04 Made of aluminum adjuvant and MPL Two components , among MPL Will adsorb on aluminum agent , Activate TLR4 reaction . GlaxoSmithKline's divalent HPV The vaccine Cervarix, This adjuvant is used .

You may not know , An excellent adjuvant , It can directly change a vaccine 、 Even the fate of a company .

Regarding this , GlaxoSmithKline has enough say . Its AS01 Adjuvants , Let the recombinant protein herpes zoster vaccine Shingrix Become the ceiling of the industry , Chop the live attenuated vaccine of MSD under the horse ; Now RSV Positive progress has also been made in vaccines , It is expected to overcome the black hole of 60 years of research and development .

Novavax Of Matrix-M New adjuvant , Green is better than blue . It not only makes recombinant protein covid-19 vaccine NVX-CoV2373 In terms of immunogenicity, it is not inferior to mRNA The vaccine ; Also let the flu vaccine in 3 Head to head ceiling Flubok（Sanofi） in , Show positive results .

Vaccine of traditional technical route , It is also revitalized by the emergence of adjuvants .

Valneva The company's inactivated vaccine VLA2001, Adding aluminum adjuvant 、CpG 1018 After mixing the adjuvant , It is effective for many variants , And in terms of immunogenicity, the emerging technology route of adenovirus vector vaccine .

Its phase III clinical head to head AstraZeneca adenovirus vector vaccine AZD1222, Final data display , Under the same conditions ,VLA2001 Neutralizing antibody titer is 862, yes AZD1222 Of 1.39 times .

Thanks to its excellent performance ,VLA2001 Become the first inactivated vaccine approved in Europe , Pull back a game for the traditional technical route .

Of course , The role of adjuvants is not limited to this . The use of adjuvants can also reduce the number of vaccinations , It is convenient for the use of small doses of antigen , Improve vaccine response ability . To make a long story short , Although adjuvant is unknown , But its role is irreplaceable .

It's just , Due to the high difficulty of research and development , For a long time , Adjuvants belong to those that no one walks on “ wasteland ”.

100 Years old 6 Payment approved , The difficulty of adjuvant research and development ？

In the vaccine industry , People's ideas are generally conservative , If not for the boost of covid-19 vaccine , The advent of new vaccine technology and new adjuvants will not come so soon .

After all , In the previous decades , The most widely used adjuvant is 1920 Aluminum adjuvant discovered in . Although it has been verified for a long time , But the traditional aluminum adjuvant is not perfect , Its induced immune response is not strong enough .

We all know , The antigen response of vaccines can be divided into Th1 and Th2 Two kinds of ,Th1 Type a response mainly leads to cell-mediated immune response ,Th2 Type a response is humoral immunity that can induce neutralizing antibody response .

Traditional aluminum adjuvants can only induce Th2 Type answer , But only this type of immune response , The protection provided for vaccines is not efficient . So induce Th1 Adjuvants of type a immune response are also the research direction of new adjuvants .

20 century 90 s , As people understand the immune system better , Other types of vaccine adjuvants have also been introduced . But compared with vaccines , The number of adjuvants on the market is still pitifully small .

Up to now , In the last hundred years FDA There are only six new adjuvants approved for marketing , Respectively MF59、AS04、AS03、AS01、CpG1018, And the new crown for emergency use Matrix-M Adjuvants .

Why is that ？

First , It's a security issue .

Adjuvants are substances injected into the human body with vaccines , Safety is naturally the primary requirement . But the difficulty lies in , A safe and effective substance , Hard to find .

And in the past , It mainly depends on personal research and development experience to design different adjuvant formulas , Virtually increased the difficulty .

At this stage , The new generation adjuvant is basically improved on the shoulders of the first generation adjuvant . even so , Development is still very difficult .

secondly , The mechanism of action of adjuvant is very complex .

all the time , Adjuvant research is known as the vaccine industry “dirty little secrets”, This is mainly because people have less understanding of the mechanism of adjuvant .

Up to now , The mechanism of action of many adjuvants , Researchers have not yet studied clearly . for example QS-21 And the mechanism of immune stimulation complex is always half understood .

This has also led to , Before, the development of adjuvant can only follow “ Empirical science ”, Be commonly called “ Three points of strength , Seven points of luck ”. Until recent years , The development of modern immunology , Especially the accumulation of innate immune knowledge , It has accelerated the development of vaccine adjuvants to a certain extent .

Last , It is the challenge of process amplification .

In these adjuvant formulas , It usually has natural derived components that are difficult to characterize and standardize , For example, squalene oil in oil in water lotion （ From shark liver ）. This leads to two problems , First, it is difficult to enlarge the process stably , Second, raw materials are hard won .

Don't underestimate this problem . Having technology is the first step , We should also have the ability to bring technology from the laboratory to the industry . Due to the process amplification of adjuvant and the supply of raw materials ,Novavax It has repeatedly postponed the date of its covid-19 vaccine application for marketing .

It is these difficult problems one by one , It limits the research and development progress of new adjuvants , As a result, it has become a scarce species in the vaccine industry .

Domestic adjuvant “ Pioneer ”, The rise of vaccines in China

Although only six adjuvants have been used in the past hundred years FDA Approval for listing , But behind every new adjuvant , Have brought about changes in vaccines .

GlaxoSmithKline relies on AS Adjuvant system , It has become a well deserved adjuvant system “ Carry the handle ”. This will also be an opportunity for domestic enterprises .

After the outbreak of the new crown , The domestic vaccine supply chain is catalysed strongly , Adjuvants are no longer unsung heroes , The development and application of new adjuvants continue to accelerate . Many players in China have begun to research and develop adjuvants , Try to break through this choked field .

For example, REC Biology , At present, REC bio benchmarked GlaxoSmithKline AS01、AS03、AS04 Three new adjuvants have been developed . At present, REC bio uses these three new adjuvants , The herpes zoster vaccine has been carried out respectively 、 New crown vaccine 、HPV Vaccine development .

among , Covid-19 vaccine with new adjuvant ReCOV Has shown initial potential , In human trials ReCOV Can induce and mRNA Neutralizing antibodies at similar or higher levels .

And living creatures , Started to develop the picaine adjuvant . Pickup adjuvant is a kind of targeted TLR3、RIG-I、MDA5 Adjuvant of receptor . It can produce costimulatory factors by activating innate immunity CD40、CD80、CD86, Promote the presentation of antigen presenting cells 、 activation T Lymphocytes , Finally, it promotes specific cellular and humoral immune responses at the same time , To get a stronger immune response .

at present , Pica rabies vaccine based on biosphere 、 Pickup HBV The vaccine is in the clinical stage . In clinical practice , Pica rabies vaccine shows stronger immune ability than the currently used rabies vaccine .

Maikekang biology also has a nano emulsion adjuvant technology platform , And compound adjuvant technology platform . at present , Its self-developed compound new adjuvant MA105 Adjuvant system , It has been used in the research and development of recombinant herpes zoster vaccine .

besides , And independently developed by vanotai HA103（QS-21） Adjuvants 、 Huapu biological CpG Adjuvants 、 Shanghai Zerun aluminum /CpG Adjuvants 、 Zhifei biological CpG Adjuvant and compound adjuvant , And Watson 、 Clover organisms have become adjuvant pioneers .

Our adjuvant industry is no longer a desert , These pioneers are ushering in their golden age , It is also supporting the domestic vaccine industry “ Golden decade ”.