Dave Hornby: Covid-19 and the road to a vaccine

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In my last post, I explained the basic properties of Covid-19 and how it relates to other well known viruses. Of perhaps the greatest concern to everyone is how science and medicine can be harnessed to beat this virus. There are currently a limited number of pharmacological ways of combating the pathological effect of a virus. The first one I am going to discuss is vaccination and in a separate post I shall focus on antiviral drugs. Antidotes represent a specialist category of medicines that are administered to reverse the effects of a toxin and I won’t discuss them here (maybe later). One small point, after a few suggestions from readers, I have tried to explain key terms as I go along. If there is no explanation (eg endosomes) I am assuming these are not essential for general understanding and can easily be found via Google, for the aficionados!

The word vaccine is itself a little unusual, if you don’t already know, it is derived from the Latin word vaccinus, pertaining to cows, which makes sense, since Jenner’s work was based around cowpox. The World Health Authority’s statement on vaccines captures the essence of their use in medicine:

“Vaccination is one of the most effective ways to prevent diseases. A vaccine helps the body’s immune system to recognize and fight pathogens like viruses or bacteria, which then keeps us safe from the diseases they cause. Vaccines protect against more than 25 debilitating or life-threatening diseases, including measles, polio, tetanus, diphtheria, meningitis, influenza, tetanus, typhoid and cervical cancer”.

The small glass vials in the above image (typically sealed with a rubber stopper) are in universal use for storing vaccines before injection. But what is inside a typical vaccine? To the pharmacist, the way in which any medicine is packaged and prepared for administration is referred to as formulation. And in the case of vaccines, you may be surprised at the formulation. In addition to the recombinant mixture of antigens (it is directed at 4 molecular variants, or quadravalent), a vial of Afluria vaccine from Seqirus for example, also contains: sodium chloride, monobasic sodium phosphate, dibasic sodium phosphate, monobasic potassium phosphate, potassium chloride, calcium chloride, sodium taurodeoxycholate, ovalbumin, sucrose, neomycin sulfate, polymyxin B, betapropiolactone, hydrocortisone thimerosal

…all of which are collectively referred to as adjuvants, or substances that enhance the immunogenicity of the vaccine’s principle component. (To be precise, some components are adjuvants and others are stabilizers, that ensure the vaccine maintains its potency under the recommended storage conditions).

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Three-dimensional structure of haemagglutinin

Of course, the key component of the vaccine is the immunogen, which is defined as an antigen that elicits an immune response. The word antigen itself is defined as a foreign molecule that specifically interacts with an antibody (you can read about antibodies at an earlier post). Antigens can be small molecules (where they are sometimes called haptens), proteins or whole cells. In the case of Afluria, the immunogens are given below by the manufacturer: each 0.5ml dose contains 15µg haemagglutinin (HA), total 60µg, from four influenza types and subtypes: A/H1N1, A/H3N2, B/Yamagata, and B/Victoria. The multi-dose vial also contains thimerosal (24.5µg mercury per 0.5ml dose). The image above on the LHS is a representation of haemagglutinin, one of the main immunogens used in influenza vaccines.

H(a)emagglutinin (UK/US spellings), as shown above projects outwards from the surface  of the virus particle. The four variants of HA (above in red) are mutants found associated with different viral strains. The quadravalent vaccine aims to eliminate all four major types of influenza in circulation. Why target haemagglutinin? To answer this  we need to understand how influenza virus acts on us. The influenza virus is shown schematically on the RHS. Covid-19 has a single major spike protein, but the flu virus has two: neuraminidase (N) and haemagglutinin. (This why you may hear of flu viruses called H1N1, which is a shorthand for a specific combination of haemagglutinin and neuraminidase sequences).

Influenza virus HA first binds to sialic acid residues on glycoproteins or glycolilipid receptors on the surface of the host cell, in response, the cell then engulfs (or endocytoses) the virus. In the acidic environment of the endosomes, the virus changes shape and fuses its envelope with the endosomal membrane. This is followed by a signal to release the virus nucleocapsid into the host cytoplasm. From there, the nucleocapsid travels to the host nucleus and a train of events has now been triggered that leads to virus replication. Here is a nice video simulation of the process. Unlike the virus itself, a vaccine will stimulate the production of antibodies that will in turn block this sequence of events by masking the HA or N proteins.

Unfortunately, these proteins are susceptible to mutation (as discussed in the previous post) and, as a result, completely new vaccines must be prepared each year. The design of each new vaccine is determined following a twice yearly international consultation and evaluation of the epidemiology of viral infection and the determination of the genome sequences of the most common viruses. The time taken for a flu vaccine to be produced just fits into the “window” between the February (northern hemisphere) decision meeting and the surge in cases typical of flu in October as can be seen from the 1918 Spanish Flu pandemic (top LHS): we are unsure yet whether Covid-19 is seasonal.

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So here’s what happens when you are injected with a flu vaccine (or any other vaccine for that matter). The formulated preparation of antigens stimulates the production (in this case ) of HA/N specific antibodies. Shortly after the injection some people experience mild flu-like symptoms, but importantly, within around 14 days, you will have produced a reservoir of antibodies that can be mobilized rapidly if you become infected with the virus in the future. You are now immune to the virus. [I shall come back to the issue of the level and the longevity of immunity later in the post.] I have given the example of influenza vaccination which is usually injected intra-muscularly, but a vaccine can be administered orally, subcutaneously (the needle penetrates the fatty tissue beneath the skin), intra-nasally (though the nose) or intra-venously. Again, each method will be associated with a specific formulation.

Last week in the journal Science, a US structural biology group used cryo-electron microscopy to determine the structure of the Covid-19 spike protein, This is/will be the major vaccination target. The spike protein makes an interaction with a protein called ACE-2 (angiotensin converting enzyme-2: this enzyme is displayed on the membrane of cells from a number of tissue types including the lung, where it plays a role in lowering blood pressure). I hope you can see from one of the images taken from the paper that the spike protein (on the right) changes shape on making contact with the target cell. The green coloured domain adopts the “up position” revealing a surface that makes a strong interaction with ACE-2. At this point, the virus is engulfed and the viral RNA makes its way into the cytoplasm where a combination of transcription (producing the mRNA needed to manufacture new viral components) and replication takes place, as the virus overwhelms the cell. The race is on to produce a vaccine against the Covid-19 virus.

The time taken to produce a new vaccine is at least 18 months (allowing for design, manufacturing, safety testing and trials) to many years. The best flu vaccines available in 2020 offer at best around 50% protection against hospitalisation as a result of flu infection. Similarly, 40 years on from the emergence of HIV and AIDS, there is currently no vaccine that will prevent HIV infection, or treat those who have it. You may have heard about the Moderna  vaccine that is currently undergoing safety testing in volunteers (Phase I Cliical Trial). The innovation here is to bypass the need to purify the protein-based immunogen (or whole virus), by direct injection of the mRNA encoding the immunogen (the spike protein). The use of mRNA as the immunogen, which in some ways mimics the way in which Covid-19 operates, was first suggested nearly 30 years ago, but only in the last 10 years has technology been available to translate this concept into clinical practice. I will be watching the outcome of this work with great interest, but the likely availability of an effective vaccine is still at least a year away: and possibly longer.

As promised earlier, I said I would mention the durability of vaccines and vaccination. In the case of seasonal flu, those who are perceived to be most vulnerable are a priority for vaccination. [You will also have no doubt heard reports of deaths resulting from Covid-19 and their “underlying conditions”.
This is a catch-all phrase to emphasise that those most likely to experience life-threatening  consequences of infection,are those with an already challenged immune system. In addition, since Covid-19  gains entry via the respiratory system, among those at high risk will be chronic asthmatics and cystic fibrosis sufferers]. The durability of an individual’s immune response seems to be variable. In addition each type of vaccine appears to show differences. There is a nice article here on the factors known to influence the longevity of a vaccine. Suffice to say though at this stage, in the absence of a Covid-19 vaccine, only time will tell.

I shall leave you with a link to a recent editorial in the journal Science, which  in my view makes some powerful and important observations on the need to ensure that we understand the underpinning Science and respect the fundamental laws of Nature that will eventually enable us to develop a vaccine. As Richard Feynman famously once said:
“For a successful technology, reality must take precedence over public relations, for Nature cannot be fooled.”