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By Lois Privor-Dumm, Naor Bar-Zeev, and William Moss for the International Vaccine Access Center

International Vaccine Access Center
This primer on Covid-19 vaccines consists of a series of brief reports on vaccine development, allocation, and deployment in the United States and globally. The intended audience is the general public as well as policymakers, educators, and key stakeholders interested in a concise guide to Covid-19 vaccines. Topics to be addressed include ensuring the safety and efficacy of Covid-19 vaccines, principles for vaccine allocation, strategies for deployment and delivery of Covid-19 vaccines, vaccine confidence and demand, and the economics of Covid-19 vaccines.
Several different types of vaccines against SARS-CoV-2, the virus that causes the disease Covid-19, are in development. Some are based on traditional methods for producing vaccines and others use newer methods.
Vaccines stimulate the human body’s own protective immune responses so that, if a person is infected with a pathogen, the immune system can quickly prevent the infection from spreading within the body and causing disease. In this way, vaccines mimic natural infection but without actually causing a person to become sick.
For SARS-CoV-2, antibodies that bind to and block the spike protein on the virus’s surface are thought to be most important for protection from disease because the spike protein is what attaches to human cells, allowing the virus to enter. Blocking this entrance prevents infection and thus disease and transmission to others.
The ideal SARS-CoV-2 vaccine would:
be safe and associated with only mild, transient side effects (e.g. soreness and low-grade fever);
confer long-lasting protection (more than a season) in a high proportion of vaccine recipients (e.g. >80%), particularly in vulnerable populations such as the older adults and those with other underlying medical conditions or risk factors such as obesity;
protect not only against disease but prevent virus transmission to others;
be administered as a single dose;
be able to be produced quickly and in large quantities;
be easily stored (e.g., not at ultra-low temperatures, in packaging that does not require a lot of space);
can be easily transported (e.g., outside of the cold-chain or even through the mail); and
can be easily administered (does not require special devices, self-administered or administered by those who do not require much training).
The initial SARS-CoV-2 vaccines will not have all of these characteristics and we may never have a vaccine that does. Different types of vaccines will have different characteristics with different tradeoffs. The most important characteristics are that a SARS-CoV-2 vaccine be safe, shortly after vaccination and in the long term, and protect a substantial proportion of those vaccinated against moderate to severe disease, particularly those in the most vulnerable groups.
Several inactivated SARS-CoV-2 vaccines have been developed, including those by Sinovac Biotech, Sinopharm, the Wuhan Institute of Biological Products, and Bharat Biotech. Inactivation of viruses is a well-established method to produce vaccines and several inactivated virus vaccines are widely used, including vaccines against influenza, polio, hepatitis A, and rabies viruses. The virus is inactivated so that it can no longer replicate or multiply. The immune system is exposed to viral proteins but the inactivated virus cannot cause disease. The inactivated virus stimulates the body’s immune system to produce antibodies so when a person is exposed to the natural virus, antibodies are called to action to fight the virus.
Production of inactivated virus vaccines requires the ability to cultivate or grow the virus in large quantities. Because viruses cannot replicate outside of host cells, vaccine viruses need to be cultured in continuous cell lines or tissues. Influenza virus, for example, is typically grown in eggs to produce the inactivated influenza vaccine. The virus is then purified and concentrated before inactivation with chemicals. Inactivated vaccines typically do not provide immune responses as strong as attenuated (i.e., modified or weakened viruses so they do not cause disease) viral vaccines and may require booster doses to achieve and sustain protection.
Inactivated virus vaccines have been produced for many decades and the manufacturing procedures are well established and relatively straightforward, although there are challenges to producing safe and effective inactivated virus vaccines. First, the inactivation process has to sufficiently inactivate all of the virus without changing viral proteins so much that they induce weak immune responses. Second, the inactivation process cannot alter the virial proteins in a way that results in an abnormal or altered immune response and enhanced disease after exposure to the natural virus. As with all vaccines, the immunogenicity of new inactivated virus vaccines must be rigorously tested to ensure safety and efficacy.
Many vaccines for SARS-CoV-2 in development include only viral proteins and no genetic material, including those by Novavax, Sanofi and GlaxoSmithKline, SpyBiotech, and others. Some use whole viral proteins and others just pieces of viral proteins. For SARS-CoV-2 vaccines, this means either the spike protein on the surface of the virus or a portion of the spike protein called the receptor-binding domain, which binds to host cells (i.e., the cells where viruses can replicate). These protein-based, or subunit, vaccines work much like inactivated vaccines by exposing the immune system to viral proteins and inducing protective immune responses without causing disease. In the case of protein-based vaccines, this is because no genes necessary for virus replication are included in the vaccine.
Protein-based vaccines have been widely used and have a long history of safety and effectiveness. Examples include vaccines for hepatitis B virus, shingles, and the bacteria that cause whooping cough (pertussis). There are different ways of producing recombinant viral proteins, including production of the virus protein in yeast or insect cells. Protein-based vaccines also can be packaged in different ways and combined with vaccine adjuvants (additives in small quantities) that improve or enhance immune responses. The Novavax SARS-CoV-2 vaccine, for example, uses nanoparticles of cholesterol, phospholipid, and saponins from the soap bark tree to deliver viral proteins to cells of the immune system and stimulate strong immune responses.
The addition of adjuvants to vaccines is another common way of enhancing the immune responses to virus proteins. Protein-based vaccines sometimes do not induce strong CD8 T cell responses, the cells that destroy virus-infected cells, and adjuvants can help correct this. Aluminum-containing adjuvants have been used in vaccines since the 1930s in small enough quantities to not cause any harm. Other adjuvants include different lipid formulations and a synthetic form of DNA that mimics bacterial and viral genetic material. Vaccine adjuvants will likely be important to induce strong and durable protection in older adults whose immune systems are less responsive as they age. Vaccines with adjuvants can cause more local reactions, such as redness, swelling, and pain at the injection site, and more systemic reactions such as fever, chills, and body aches, than non-adjuvanted vaccines.
Viral vector vaccines use another non-replicating virus to deliver SARS-CoV-2 genes, in the form of DNA, into human cells where viral proteins are produced to induce protective immune responses. This viral DNA is not integrated into the host genome (i.e.., all of the body’s DNA) but is transcribed or copied into messenger RNA and translated into proteins. Current SARS-CoV-2 viral vectored vaccines use non-replicating human or chimpanzee adenoviruses, including those by AstraZeneca with the University of Oxford, Johnson & Johnson, CanSino Biologics, and the Gamaleya Research Institute, part of Russia’s Ministry of Health.
Adenoviruses are a group of approximately 50 common viruses that can cause cold-like symptoms, fever, sore throat, diarrhea, and pink eye. The human adenovirus vectors used for SARS-CoV-2 are weakened forms of adenovirus 5 and adenovirus 26. The weakened vectors do not replicate because important genes have been deleted. These vaccines will likely require at least two doses, although there is some hope that a single dose may induce protective immune responses.
Viral vectors have been studied for several decades for gene therapy, to treat cancer, and for research into molecular biology as well as for vaccines. Viral vectors other than adenoviruses include retroviruses and the vaccinia virus that was used to prevent smallpox. In July 2020, the European Commission approved use of an adenovirus 26 vaccine for Ebola that was manufactured by Johnson & Johnson, the first adenovirus vectored vaccine approved for use in humans, and the same vaccine platform used by Johnson & Johnson for their SARS-CoV-2 vaccine. Large-scale production of viral vector vaccines requires cultivation of the viral vector, such as adenovirus, in cell cultures and virus purification.
Most people have been exposed to multiple adenoviruses and thus have pre-existing immunity that could impair vector entry into host cells. This is a potential limitation of viral vector vaccines using human adenoviruses. The AstraZeneca and University of Oxford vaccine uses a chimpanzee adenovirus as vector, thus minimizing the risk of pre-existing immunity to the vector that might reduce vaccine efficacy.
Instead of using a viral vector to deliver SARS-CoV-2 virus genes to human cells, the genes can be administered directly as either DNA or RNA. Several of the SARS-CoV-2 vaccines furthest along in phase 3 trials are messenger RNA (mRNA) vaccines that deliver the spike protein gene, including those by Moderna, BioNTec with Pfizer, CureVac, and Imperial College London. Once the genetic sequence of the SARS-CoV-2 virus was known in January 2020, it was relatively straightforward to generate genetic vaccine candidates. mRNA vaccines are easier to develop and manufacture compared to other vaccine types as they do not require cultivating viruses in cells. This is why they were some of the first SARS-CoV-2 vaccines to enter human trials. However, no mRNA vaccine has previously been licensed and approved for humans and most experience with this technology in humans has been for the treatment of cancer.
mRNA vaccines are taken up into cells, but do not need to enter the nucleus to trick the body into producing viral proteins, which then induce immune responses. RNA is particularly potent at inducing innate immune response, the earliest type of response to a pathogen that prevents spread within the body. mRNA is used by the cell as a template to build a protein through the process of translation.
Early phase 1 and 2 studies of SARS-CoV-2 mRNA vaccines show these vaccines induce immune responses likely to be protective, including in older adults. However, until phase 3 clinical trials are completed, the safety, efficacy, and duration of protection from mRNA vaccines will not be known and at least two doses will be required.
Until completion of the phase 3 clinical trials, we will not know the safety and efficacy of the different types of SARS-CoV-2 vaccines and their relative advantages and disadvantages. It will be important to not only monitor short-term vaccine safety, such as soreness and fever, but the risk of long-term adverse events such as enhanced disease following exposure to natural infection and autoimmune diseases. Of particular interest will be vaccine effectiveness in vulnerable populations such as older adults and those with underlying medical conditions, including diabetes, HIV infection, and chronic heart, kidney, and lung diseases. Protein-based vaccines with adjuvants may be the most likely to induce protective immune responses in elderly adults with weakened immune systems. These different vaccine types will not be interchangeable. Once a vaccine is selected, the same vaccine must be used for a second dose if required.
Many of the vaccines furthest along in development are those for which vaccine delivery platforms existed. mRNA vaccines were developed rapidly after the SARS-CoV-2 genome was sequenced and manufacturing capacity can be rapidly scaled-up. However, some mRNA vaccines have stringent cold chain requirements. The Pfizer and BioNTech mRNA will need to be stored at -70oC until about 48 hours prior to use, when it can be refrigerated, because of the instability of RNA, while the Moderna mRNA vaccine may require storage at -20oC until about one week prior to use. Freezers with the capacity to hold large volumes of vaccine at this temperature will be needed and are not currently part of the existing vaccine supply cold chain.
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