What really is the best vaccine out there?
Dr. Edsel Maurice T. Salvana
The global push for safe and effective vaccines against COVID-19 has led to a bumper crop of vaccine candidates. With over 200 COVID-19 vaccines in development and at least 10 vaccines completing or about to complete phase 3 clinical trials, which vaccine is the best?
In last week’s column, I emphasized that for those in imminent danger of severe COVID-19 should get vaccinated as soon as possible with whatever properly approved vaccine is available. This will be the case in the short term as global demand outstrips supply. As supply chains catch up and more vaccines are proven to work, we will get to the point where we can choose the most appropriate vaccine for each of us.
NEEDLE IN THE HAYSTACK Dr. Nita Patel, Director of Antibody discovery and Vaccine development, lifts a vial with a potential COVID 19 vaccine at Novavax labs in Gaithersburg, Maryland on March 20, 2020 (Andrew Caballero-Reynolds)
COVID-19 vaccines fall under one of six categories. These are the categories.
a. Nucleic acid-based vaccines use viral genetic material, whether RNA or DNA. This includes the mRNA vaccines like Pfizer and Moderna.
b. Inactivated virus vaccines use killed whole virus. This vaccine type includes Sinovac and Sinopharm vaccines.
c. Recombinant viral vectored vaccines use a harmless live virus as a carrier for the target virus’ genetic material to induce an immune response. Current COVID-19 vaccines using this technology use live but non-replicating carrier viruses like adenovirus 5 or adenovirus 26. Examples are vaccines from Astra, Cansino, J&J, and Gamaleya.
d. Protein subunit vaccines use a piece of the virus, usually the spike protein, to generate an immune response.
e. Virus-like particle vaccines use artificial construct or structure that mimics real viruses and the body’s immune system responds accordingly.
f. Live attenuated virus vaccines use a weakened form of the target virus to induce the immune response.
Each of these categories come with advantages and disadvantages. Broadly speaking, only live attenuated viruses are able to reproduce. Recombinant viral vectors are alive, but are not able to reproduce. The rest of the vaccines are neither live nor able to replicate. These vaccine characteristics have important implications on the ability of the vaccine to produce robust immunity. This also impacts which patient populations can be safely inoculated with them.
Live replicating virus vaccines
Live attenuated COVID-19 vaccines are still in development and are not yet in clinical trials. This kind of vaccine is the most likely to be transmission-blocking because they mimic natural infection better than any of the other vaccines. These vaccines, however, are also the ones that can rarely inadvertently cause a form of the disease in susceptible hosts.
The oral polio vaccine (OPV) is an example of a live attenuated vaccine. OPV worked so well that natural polio infections were nearly eliminated. Once the level of natural polio infections drastically dropped due to the potency of OPV, the number of people who developed an atypical form of polio from the OPV outnumbered the ones who actually got polio from natural infection. This is why in places where polio cases are low, the recommended polio vaccine is switched to inactivated polio vaccine (IPV). This is because IPV does not have the danger of inadvertently causing an atypical form of polio and its main effect is to prevent the severe form of polio. IPV, however, does not block polio transmission. When there is a polio outbreak, live OPV is deployed to block transmission and extinguish the outbreak.
There is a lot of interest in live attenuated SARS-CoV-2 vaccines because these may be the ones that are more likely to generate herd immunity by being transmission blocking. They may also work better in children since kids have immature immune systems and may require a more robust active ingredient in a vaccine.
Live non-replicating virus vaccine
The Astra, Cansino, J&J, and Gamaleya vaccines all use modified adenoviruses. These viruses are engineered to be unable to reproduce in humans but they contain part of the genetic sequence of the SARS-CoV-2 spike protein or other viral parts. The adenovirus inserts the target genetic sequence into the host cell, which then makes virus parts that are recognized by the immune system. Using a live vector produces a whole gamut of immune responses, which may lead to more robust and longer-lasting protection.
Using a non-replicating virus as a carrier is safer than a live attenuated virus because there is virtually no possibility of the carrier virus causing the actual disease. Live vaccines, however, even non-replicating ones should be used with caution among patients with weakened immune systems. These patients may not be able to overcome the live vaccines and may inadvertently develop disease if their body is unable to control even a weakened virus. Non-replicating viral vector vaccines are still relatively new, and so these should still be used with caution among people with diminished immune responses.
Non-live non-replicating
The rest of the vaccine types are not live and are not replicating. These vaccines are considered safe even for people with underlying immune problems. One disadvantage is that some of these vaccines, such as the inactivated virus or protein subunit vaccines, may not induce as strong an immune response as the live vaccines.
Virus-like particles (VLPs) and mRNA vaccines address this problem using novel delivery mechanisms and innovative techniques. VLPs use recombinant technology and have been used in the human papilloma virus (HPV) vaccines against cervical cancer. These mimic real viruses by maximizing immune responses but eliminate the risk of using a live virus.
Nucleic acid-based vaccines like mRNA vaccines are not a new concept but the difficulty has been in ensuring that the nucleic acid molecules get into the cells intact. Once inside the cell, the body processes the mRNA into proteins and these proteins trigger the immune response. Our body makes millions of copies of proteins from our own mRNA, and the added protein production from an mRNA vaccine is a mere fraction of what the body handles in a day. The effectiveness of mRNA vaccines is from the large number of protein particles it generates. These proteins find their way into both the intracellular and extracellular compartments and induce a robust immune response. Allergic reactions that are seen in some people may be due to the novel lipid nanoparticle carriers used rather than the mRNA itself. These allergic reactions are being thoroughly investigated to identify any specific risks. Otherwise, mRNA vaccines are reasonably safe and effective.
The main advantage of using inactivated whole virus vaccines is that this is reasonably safe and proven technology.
These, however, may not induce as robust an immune response compared to live viruses. The ability to block transmission and mild disease may not be as high as that of live vaccines or mRNA vaccines. Nonetheless, the ability to prevent severe disease means that these vaccines may be best used for very frail people who need protection from severe disease but may not be able to tolerate live vaccines or the exuberant immunogenicity of mRNA vaccines. One other advantage of using the entire deactivated virus over using pieces or parts of it (VLPs, mRNA, protein subunit, recombinant vector) is that there is a large diversity of antigens available to induce an immune response. This large repertoire of antibodies may render the vaccine more resistant to escape mutations from the emerging new variants.
There remain a lot of unknowns on how the different types of vaccines work against COVID-19.
One of the most important questions is how long the protection will last. The longest amount of time that trial subjects have been observed from the early phase one trials is less than one year. We won’t know until after a year has passed whether these vaccines will need a booster later. The emergence of vaccine escape mutations is a concerning development. Vaccines can be “fixed,” however, by incorporating new sequences and new variants into the existing vaccines.
The plethora of vaccines being developed for COVID-19 can sometimes confuse people and make them more vaccine hesitant. At this time, there is no “best” vaccine and there is no “more appropriate” vaccine since we still have very little data. For the most at risk, especially frontliners and the elderly, the best vaccine is the vaccine you can get as soon as possible. When a vaccine is offered to you and you have questions, talk to your doctor about your risk and whether you can afford to wait or not. Don’t let fear or uncertainty take away our best shot at defeating COVID-19 once and for all.