How are vaccines made?

The immune system consists of the innate and acquired immune systems. The former is what you are born with, and it swings into action immediately on invasion by a recognized pathogen. Cells called phagocytes surround and engulf the invader and clear the infection. 

The acquired immune system involves the antibodies and swings into action when a novel pathogen is encountered. Antigen presenting cells (APCs) engulf the pathogen and set of T-helper cells which in turn activate B-lymphocytes. These produce antibodies which prevent the pathogen from invading healthy cells. Cytotoxic T cells are also triggered which engulf already infected cells. 

An important difference between innate and acquired immunity is that the former is triggered right away, whereas the latter takes several days to kick in. This is because the system needs time to appropriately identify antigens and produce antibodies in bulk to counter the invasion. However, the body acquires immunity to the novel pathogen since this process triggers the development of memory B and T-cells. These are activated much faster when the pathogen is encountered again and the immune system swings into action to prevent a long standing, or potentially deadly infection. 

Vaccines attempt to mimic this process without causing the disease, or a very mild version of the disease, by using a weakened pathogen or its subunits. It is therefore called ‘passive immunity’ since the immune response is not developed by the immune system per se but by a triggering mechanism that brings about long-term immunity cells without directly battling the pathogen. 

Many types of vaccines, and especially live vaccines, require additional or booster shots to maintain immunity levels. There are exceptions, of course-- the flu vaccine is updated yearly based on what is predicted to be the most virulent and prevalent of strains at the time. Also, immunity from flu vaccines is usually short lived and needs to be replenished to have desired effects. 

Vaccines may also come with adjuvants-- substances that enhance vaccine effectiveness and boost immune responses. They do this by broadly enhancing the effect of antigen identification. Another advantage is that adjuvants reduce the amount of antigens needed to manufacture vaccines which can be crucial in times where there is a shortage of them. 

Here is a look at the several different types of vaccines and their use in the scramble to develop a working version that can change the course of the COVID-19 pandemic.

Originally vaccines were whole pathogen vaccines which means that they used an inactivated or weakened version of the pathogen to elicit an immune response without causing the disease. Even today many vaccines follow this basic principle. The advantage with this approach is that it usually confers strong, long term immunity. However, extensive safety studies need to be conducted to make sure the vaccine does not have adverse side effects. 

While it is tempting to assume that all sorts of infectious diseases can be combated in this manner, whole pathogen vaccines do not show as much of a response with complex bacterial diseases and are more effective with viral infections. 

Whole pathogen vaccines are inactivated vaccines or live attenuated vaccines. In the former, the pathogen is killed using chemicals such as formaldehyde or heat. The hepatitis A vaccine is a common example of an inactive vaccine. 

A drawback of this technique is that it requires large quantities of the infectious virus. According to the WHO, 4 out of the 10 vaccines that are in the clinical trial stage are inactivated vaccines. 3 of these, all under Chinese leadership, are entering stage 2 trials. 

Live-attenuated viruses consist of pathogens that are weakened but not killed. The MMR vaccine is perhaps the most popular live attenuated vaccine. Two Indian enterprises, Serum Institute of India and Indian Immunologicals Limited, have partnered with foreign entities to develop live attenuated vaccines. They are currently in the preclinical stage, however.

These vaccines are unique in that they do not contain the entire pathogen but only the components, or antigens, that stimulate an immune response. They do require the use of adjuvants to boost the immune response since the limited number of antigens used is often not sufficient to manage a sustained response. The pertussis (whooping cough) vaccine is an important example of the subunit vaccine. 

Recombinant protein vaccines are an example of subunit vaccines that use genetic engineering to combine different strands of protein to make a vaccine that can provide more sustained immunity. 

Novavax is using a protein subunit vaccine with recombinant technology and an adjuvant. 

Another subunit vaccine method that has gained some popularity is technology involving virus like particles (VLPs). This involves using the outer shells of a virus against which the immune system will mount an immune response. Since the outer shell does not contain the virus, there is no risk of infection. At least five teams are trying this method, but they are all in the preclinical stage. 

This is a promising approach that is in the pipeline of current COVID-19 vaccine development. It involves using the genetic material encoding the antigens against which a response is sought. This in turns churns out proteins that would have been released by the pathogen, and the immune system uses this to mount an attack. The advantage with this method is that the actual virus does not need to be used-- just the genetic material that codes for some harmless proteins associated with it. This technology has not been licensed for human use yet, but some animal studies involving the Zika virus have been promising. 

In the case of Covid, almost all developers are focusing on the proteins that code for the ‘spike’ protein which the virus uses to enter normal cells. There are DNA and RNA vaccines. In the former, a DNA plasmid coding for a part of the pathogen is used whereas in the RNA vaccine, mRNA that codes for a component of the pathogen is used. 

The US firm Moderna is using the mRNA, and it has reached stage 2 trials so far. Moderna was one of the first firms to set up human trials and has received a lot of funding the US NIH-- a lot of people have placed their hopes on this vaccine.

Inovio and Pfizer are the other firms using nucleic acid vaccines that have progressed to clinical trials.

What makes this approach unique is that rather than directly delivering DNA or mRNA directly to cells, a harmless virus or bacteria is used as a vector instead. Again, the viruses are weakened so that they do not affect an adverse reaction and end up causing the disease itself.

There are two types: replicating and non-replicating virus vectors. The former replicates within cells while the latter does not; the measles vaccine is an example of a replicating vector virus, and currently no non-replicating virus vectors exist for humans. 

Having said that, the Chadox vaccine developed by Oxford and AstraZeneca uses non-replicating vector virus technology and is the only vaccine that has entered stage 2b/3 trials. If stage 3 trials work, there is a chance that we may have a vaccine by the end of the year. CanSino Biological Inc. in collaboration with Beijing Institute of Biotechnology uses the same approach and has arrived at stage 2 trials so far. The vaccine candidates for MERS and a new vaccine developed for Chikungunya has also been developed; the latter has shown some promise.

There are other types of vaccines as well, but they are used specifically for bacteria. While they have been forced into the background because of COVID-19, here is a quick a look at them.

Certain bacteria release toxins in the body. Toxoids are weakened or attenuated forms of the toxic product(s) released into the body as the result of infection. These vaccines therefore don’t attack the pathogen itself, but the toxins it releases. The DTaP vaccine, which vaccinates against diphtheria and tetanus is a common example.

There are some types of bacteria that have antigens with an additional coating of sugar molecules called polysaccharides. This extra coating makes it challenging for the body to identify the antigen and mount an immune response. Conjugated vaccines act on these polysaccharide coverings by attaching protein antigens to them that are easily recognized. This makes the pathogen easily recognizable and the body is able to overpower it. Conjugate vaccines are used against Haemophilus influenzae type B (Hib) and pneumococcal and meningococcal infections.