Covid-19 vaccines – the current state of play and the problems to overcome

Governments around the world are desperately holding out for an effective vaccine to SARS-CoV-2 , but how close are we? What are the problems, and will it be safe or effective when it does arrive? And will people take it?

Governments the world over are desperately balancing local and regional lockdown implementation and their effect on economies, justifying their necessity ‘until a vaccine becomes available’.

But what types of vaccine are likely to be available? Will they be safe? Will they work? Can they even be manufactured in enough quantity?

There are almost 200 vaccines for this virus in development, but only nine have reached the stage of Phase III clinical trials.

It is worth noting that traditional vaccine development takes a long time and a development time of 15 years is common.

The process starts with exploratory work on vaccine design and evaluation in animal models, which can take years. This is then followed by a stage in which more formal preclinical experiments are conducted, a process for vaccine production is designed and formal toxicology studies are performed, a process that can also take several years. After that stage, an application for an investigational new drug (IND) is filed and Phase I clinical trials (testing in <100 individuals, approximately 2 years) are performed to test initial safety and to obtain some immunogenicity data. If the results are promising and funding is available, a vaccine candidate is then moved into Phase II clinical trials (testing in a few hundred individuals, also about 2 years) to determine immunogenicity, dose and optimal vaccine regimens. If the results of Phase II are promising, the decision might be made to move forward with very costly Phase III trials (in thousands of individuals, approximately 2 years) in which efficacy and safety are evaluated. If the results of the Phase III trials meet the pre-defined endpoints, a biologics license application (BLA) is filed with regulatory agencies (e.g. FDA or EMA). The licensing process can take another 1-2 years, especially if additional data is requested.

The front runners

The current leading candidates are SinoVac’s Coronavac inactivated vaccine; CanSino’s AdV5-based vaccine; AstraZeneca’s ChAdOxnCoV-19 replication inactive vaccine; Moderna’s mRNA-1273; Novavax’ NVX-CoV2373 recombinant protein vaccine; Pfizer’s BNT162b1 and BNT162b2 mRNA vaccines. (Full definitions of the different types of vaccine platforms can be found at the end of this article).

Safe and effective?

These are really the front runners to produce the first licensed vaccine, and when evaluating them we can observe a gradient of immunogenicity (how effective they are at producing the targeted immune response) in this case the stimulation of neutralizing antibodies. Inactivated and AdV5 vaccines are on the lower end of the gradient, meaning that they produce a lower immune response. ChAdOx and the mRNA candidates are placed in the medium range, and the recombinant protein vaccine is at the high end.

The other major factor is that of tolerability, the ability to tolerate adverse reactions to the vaccine when injected. By this measure, the inactivated vaccines and recombinant protein vaccines seem to perform relatively well, followed by the mRNA vaccines which show increased reactogenicity after the second vaccination, followed by the AdV vectored vaccines having the most reactogenicity.

The most common side effects, for example, with Astra Zeneca’s Oxford vaccine were fatigue (>70%) and headache (>60%), and fever was also relatively common. Clearly, any long term side effects cannot be evaluated when working within current short timescales for a Covid-19 vaccine. This raises the point of public trust in the vaccine and resultant vaccine uptake. If the uptake is low, then the end value of the vaccine is questionable. Polls from the US indicate that only 50% of people would take the vaccine if it were offered. Government and health agencies are already working hard at crafting a variety of public messages and campaigns to encourage maximum vaccine uptake.

Tolerability is important, especially when considering vaccinating children since they usually show more reactogenicity. Given that many of the vaccine candidates have relatively strong side effects, low dose vaccines might be needed for this age group, especially for AdV and mRNA based vaccines.

Phase III trial results need to show that the vaccines are effective and safe in a larger population. Currently, based on NHP (Non Human Primate) data (and on a small study on a fishing vessel) it is speculated that neutralizing antibodies could be a correlate of protection. However, this still has to be shown in humans, and other factors including cellular immune responses might play a protective role as well.

No vaccine for the Upper Respiratory Tract (URT)?

Another big issue is that most vaccines will only protect from lower respiratory tract infection but might not be inducing sterilizing immunity in the upper respiratory tract. This is very important because this could lead to vaccines that, while protecting from symptomatic disease, might still allow for transmission of the virus. Sterilizing immunity in the URT would obviously be preferred, as this would greatly diminish any viral spread. Live attenuated vaccines or viral vectors that can be applied intra nasally would likely also lead to a strong mucosal immune response. Unfortunately, very few vaccines suitable for intranasal vaccination are being developed and none is in clinical trials at the time of writing, although there is a strong candidate being developed in Italy, which I reported on some weeks ago.

Immune for how long?

In addition, crucially, we do not know how long vaccine immunity will persist. Currently, we see what looks like a ‘normal’ immune response after natural infection with some of the vaccine candidates. It is at this time unknown if vaccine induced immune responses are longer or shorter lived than immune responses induced by natural infection.

The most at risk

Another unknown is how well elderly individuals, the population most at risk, will respond to the vaccine. From the Sinovac inactivated vaccine and from Pfizer’s two mRNA candidates it is clear that they respond less well and different vaccine formulations or even special prime-boost regimens might be needed to drive up immune responses in this age group. Of note, elderly individuals often need to achieve higher neutralization titers than younger individuals, at least for protection from influenza virus. Stronger vaccines or more doses come with greater possible adverse reactions in an already more vulnerable population.

Potentially, vaccine with higher reactogenicity that might induce a stronger interferon/antiviral response (mRNA vaccines, AdV vectors or even VSV-vectored vaccines) might improve titers in this age group. In addition, high dose vaccines or different vaccine type prime boost regimens (e.g. a virus vectored prime followed by an adjuvanted protein vaccine boost) have been successfully used to increase immune responses for influenza virus vaccines and could be used for SARS-Cov-2.

On the positive side, reactogenicity of Pfizer’s BNT162b and BNT162b1 vaccines was reduced in older adults making them more suitable for this age group.

How do you make 16 billion doses of vaccine?

Assuming that two shots per person are needed, 16 billion doses of vaccine have to be produced. There is high diversity in terms of vaccine platforms and geographic location of the producers since no single company will be able to produce the hitherto unimagined amount of vaccine needed.

Logistical problems

Even supply of syringes, glass vials etc. might become a bottleneck (excuse the pun) because of this huge number of doses. A specific concern here is that vaccine producers that have never before licensed a vaccine and produced it at large scale for the market (e.g. Moderna or Novavax), or vaccine based on platforms that have never been produced at large scale for the market (mRNA, DNA). Suring scale up, manufacturing and distribution of these candidate’s unforeseen challenges may arise due to limited experience with technologies or organizational structures. In the case of mRNA vaccines, the need for frozen storage and distribution already provides challenges, especially in low income countries were even regular cold chains are hard to maintain.

In terms of immunogenicity, AdV5-based vaccines seem to rank lowest, followed by inactivated and ChAdOx1 based vaccines, mRNA vaccines, and finally adjuvanted, protein-based vaccines performing best. Reactogenicity seems lowest in inactivated and protein based vaccines, followed by mRNA vaccines, with vectored vaccines having the highest rate of side effects. It is highly likely that the AstraZeneca, Moderna and Pfizer vaccine candidates, which are along the furthest in the US and Europe, all show sufficient efficacy and will be licensed if sufficiently safe. However, it may also be that these vaccines will later on be replaced by vaccines that show similar efficacy but have reactogenicity profiles that are more tolerable.



Types of vaccines in development

The platforms can be divided into ‘traditional’ approaches like inactivated or live virus vaccines, platforms that have recently resulted in licensed vaccines (recombinant proteins, vectored vaccines) and platforms that have never been used for a licensed vaccine (RNA and DNA vaccines).

Inactivated vaccines

Inactivated vaccines are produced by growing SARS-CoV-2 in cell culture, usually on Vero cells followed by chemical inactivation. These vaccines are usually administered intramuscularly and might be adjuvanted with alum or other adjuvants. Since the whole virus is presented to the immune system, immune responses are likely to target not only the S spike but also the matrix, envelope and nucleoprotein.

Live attenuated vaccines

Live attenuated vaccines are produced by generating a genetically weakened version of viruses that replicate to a limited extent, cause no disease but induce immune responses that are similar to the immune response induced by natural infection. An important advantage of these vaccines is that they can be given intranasally and induce mucosal immune responses which can protect the upper respiratory tract, the major entry portal of the virus.

Recombinant protein vaccines

Recombinant protein vaccines can be divided into recombinant S vaccines, recombinant RBD vaccines, and virus like

particle (VLP) vaccines. These recombinant proteins can be expressed in different expression systems including insect cells, mammalian cells, yeast and plants. RBD-based vaccines can likely also be expressed in E. coli.

Replication inactive vectors

Replication inactive vectors represent a large group of vaccines in development. These are typically based on another virus that has been engineered to express the S and has been disabled from replication in vivo by deletion of parts of its genome. The majority of these approaches are based on adenovirus (AdV) vectors but modified vaccinia Ankara, human parainfluenza virus vectors, influenza virus, andeno-associated virus (AAV) and Sendai virus are used as well.

Replication active vectors

Replication active vectors are typically derived from attenuated or vaccine strains of viruses that have been engineered to express a transgene, in this case the S protein. In some cases, animal viruses that do not replicate efficiently and cause no disease in humans are used as well.

Inactivated virus vectors

Some vaccines in the pipeline rely on viral vectors that display S on their surface but are then inactivated before use. The advantage here is that the inactivation process makes the vectors safer since they cannot replicate,  even in an immunocompromised host.

DNA vaccines

DNA vaccines are based on plasmid DNA that can be produced in large scale in bacteria. Typically, these plasmids contain mammalian expression promotors and the S gene which is expressed in the vaccinee upon delivery.

RNA vaccines

Finally, RNA vaccines are a relatively recent development. Similar to DNA vaccines, the genetic information for the antigen is delivered instead of the antigen itself. The antigen is then expressed in the vaccinee’s cells. Two technologies exist: Either mRNA (messenger RNA with modifications) or a self-replicating RNA are used.