Third-Generation Vaccines Take Center Stage in Battle Against COVID-19

The biopharmaceutical industry is at the forefront of COVID-19 news due to major advances in vaccine development. Now, more than a year since the first case of COVID-19 and nearing a year since daily life has been upended by the pandemic, hopes for a return to normal rest largely on the effectiveness of mass vaccination against SARS-CoV-2, the virus that causes COVID-19. In the past month, results from Phase 3 clinical trials have been reported for three vaccine candidates: one from Pfizer, in collaboration with BioNTech; one from Moderna, in collaboration with the National Institutes of Health (NIH); and one from AstraZeneca, in collaboration with Oxford University.

In the normal course of a disease, a person who is infected by a virus would, over a period of days or weeks, generate an immune response to destroy the infection and recover from illness. This immune response — particularly, proteins called antibodies that identify specific invaders — would last for months or years afterward and provide immunity from new infections of the same virus. The purpose of a vaccine is to provoke this immune response and gain the resulting immunity, without having to be infected by the actual virus first.

Vaccines work by simulating a viral infection and causing the immune system to generate antibodies specifically against the targeted virus. The effectiveness and duration of this immunity can vary greatly depending on the virus, the vaccine and the recipient. There are a number of different types of vaccines, which can be grouped in a few categories as described below.

First-generation vaccines make use of the entire virus that is being targeted. To prevent a full-blown infection when administering such a vaccine, the virus is either weakened (attenuated) by growing it in another species, forcing it to evolve away from a form that optimally targets humans, or inactivated by heat or chemicals, so that the vaccine includes the viral proteins that provoke an immune response but the proteins are not assembled into an infectious form. Examples of attenuated vaccines include measles, mumps and rubella vaccines, while inactivated vaccines include the polio, hepatitis A and rabies vaccines.

Second-generation vaccines take advantage of molecular biology techniques to include specific viral proteins or protein fragments in the vaccine instead of a whole virus. Scientists can select the portions of the targeted virus that are predicted to provoke the most effective immune response, while avoiding the risks that come from injecting an intact virus into a patient. A vaccine with only select parts of viral proteins, referred to as protein subunits, is called a subunit vaccine, and is used for example in hepatitis B vaccines. Other vaccines include the entire intact protein structure of a virus but without any genetic material inside, rendering it incapable of replicating; this is called a virus-like particle (VLP) and is used for example in human papillomavirus (HPV) vaccines.

However, there are new, third-generation vaccines that are at the forefront of the COVID-19 vaccine race. Instead of mass-producing viruses or viral proteins in the lab, an alternative approach is to vaccinate a patient with genetic material — RNA — that encodes for the desired viral protein target. In the case of SARS-CoV-2, the target that researchers have decided is the most promising is the spike protein, a protein on the surface of the virus that enables it to invade host cells. The recipient’s own cells will read the RNA encoding the SARS-CoV-2 spike protein and produce the protein, which will then provoke an immune response since the spike protein will be recognized by the immune system as foreign. This approach effectively outsources the work of producing the proteins from the lab to the patient, which offers a number of advantages, including speeding up vaccine development time.  

Another type of third-generation vaccine makes use of a relatively harmless, unrelated virus called adenovirus, which has been engineered to carry DNA encoding the desired viral protein target (such as the SARS-CoV-2 spike protein). Adenoviruses are common in humans and are one typical cause of the cold. The adenoviruses chosen for vaccines are selected to be innocuous to recipients while provoking a strong immune response — in effect raising an alarm in order to bring more attention to the invader. This may create greater immunity against the SARS-CoV-2 proteins generated by the recipient’s cells compared to providing the SARS-CoV-2 RNA alone.

Virtually every vaccine technique is being employed in the wide-ranging effort to find a candidate that is effective in preventing COVID-19. But it is these third-generation techniques that have generated the first results: both Pfizer and Moderna use RNA vaccines, while AstraZeneca uses an adenoviral vector vaccine. Full data sets from their Phase 3 clinical trials are not yet available, but so far the reported efficacy — the relative number of participants who received a placebo and then contracted symptomatic COVID-19, compared to participants who were vaccinated and contracted symptomatic COVID-19 — exceeds expectations.

Both Pfizer and Moderna report about 95% efficacy from their trials. AstraZeneca tested two different dosage regimes, one of which showed 90% efficacy and the other 62%, with an average efficacy of 70%. Many important questions remain to be answered. These include how long the resulting immunity lasts and how the vaccine affects, if at all, not just symptomatic illness but asymptomatic infection and spread.

Besides efficacy, there are logistical issues that will determine how these vaccines are deployed. For example, the formulation of the Moderna vaccine is such that it is stable for long-term storage at –20 °C, a standard freezer temperature, and short-term storage at 4 °C, a standard refrigerator temperature. In contrast, the Pfizer vaccine must be stored and transported at –80 °C, which requires specialized freezers. And while AstraZeneca’s vaccine may have lower efficacy than Pfizer’s or Moderna’s, it can be stored long-term at refrigeration temperatures, making it easier to distribute.

It is expected that more vaccines will be announced in the future by the many companies developing their own candidates, and a combination of these will be necessary to meet the massive global need.

Pfizer and Moderna have applied for emergency FDA authorization for their vaccines and, if approved, are expected to receive authorization around mid-December. Many challenges remain in implementing mass vaccination, including mass manufacturing and distribution, as well as convincing enough individuals to get vaccinated on an unprecedented scale and timeline. But getting to this stage, more quickly than would have been thought possible a year ago, is a credit to the mobilization of the biopharmaceutical industry in response to the COVID-19 pandemic.