Vaccine Basics and the Development and Rollout of COVID-19 Vaccines

Innate and Adaptive Immunity

The human body fights infections using two basic immune mechanisms called innate and adaptive immunity. Innate immunity is the body’s first line of defense and is activated immediately within minutes to a few hours of the entry of pathogens. Macrophages and neutrophils are recruited to quickly engulf and destroy extracellular pathogens by phagocytosis. Pathogen recognition is achieved in an antigen-specific manner using related molecular structures called pathogen-associated molecular patterns (PAMPs). PAMPs are broad patterns made up of essential polysaccharides and polynucleotides found in various pathogens, but these are absent in the host receptors. In innate immunity there is no memory trigger of past exposures. “Natural antibodies,” which are evolutionarily selected immunoglobulins based mostly on germline sequences, also play a role in innate immune mechanisms.

Adaptive immunity is a tailored, precise, and specific response to pathogen entry. The body mounts an initial adaptive immune response over a period of a few days to weeks. The pathogen is recognized precisely by receptors that are generated by a random process of differentiation of B and T lymphocytes. Clones of highly specific T lymphocytes that can discriminate between even very small differences in the molecular structure of pathogen epitopes are generated and recruited for the adaptive immune response. The pathogen epitopes are made of polypeptides or polysaccharides and represent the uniqueness of a pathogen. A primary adaptive B-cell response takes about a week to be detected, but the memory of the event is retained and a secondary response typically has a shorter lag phase of 3 or 4 days. Moreover, in the primary response, low-affinity immunoglobulin M (IgM) antibodies predominate initially followed by the development of higher affinity IgG antibodies. High-affinity IgG antibodies dominate the secondary response. The kinetics of the initiation of an adaptive T-cell response follows a similar time course with the ability to detect expansion of T cells, with a T-cell receptor repertoire being first detectable 3 to 4 days after pathogen challenge. Fig. 18.1 presents a depiction of the primary and secondary immune response curves. Fig. 18.2 shows the interaction of innate and adaptive immune systems. The dendritic cells act as intermediaries between the innate and adaptive immune systems. The interested reader is referred to publications by Punt et al. and Virella for further details.

Population Immunity

In vaccinology, the concept of population immunity, also referred to as herd immunity, ^a

a Because herd pertains to nonhuman primates and animals, we prefer to use population immunity.

plays a significant role. When a community attains population immunity, it can be expected to be protected from the onslaught of a specific pathogenic infection. One way to obtain this type of immunity is by the natural course of disease transmission when a significant proportion (60%–95%) of individuals in a community are exposed and subsequently get infected by the pathogen. However, this can impose a high burden of mortality and morbidity on the population. A much more desirable approach to attain population immunity is through vaccination or immunization. However, the proportion of a population in a community or geographic region who must be immunized with a vaccine for a specific infectious disease depends on the transmissibility of the pathogen in question. For example, measles is a highly contagious disease, and for effective protection, 95% coverage is needed. This is to ensure that the entire population is shielded from the pathogen. Population immunity confers a direct protective effect on the immunized, but it also provides indirect protection for the nonimmunized individuals by disabling the transmission chain, as shown in Fig. 18.3 .

History of Vaccines

From a functional perspective there are two predominant categories of vaccines: prophylactic and therapeutic. Prophylactic vaccines are typically administered as part of a preventive strategy before a person is exposed to a pathogen or develops the disease. Therapeutic vaccines are administered as a treatment strategy for an existing disease or clinical condition.

Edward Jenner is credited with developing an approach to smallpox vaccination in 1796 using anecdotal evidence and previous observations that milkmaids who developed cowpox lesions were protected from smallpox. Although Jenner is properly credited for his investigations, publications, and prolific correspondence that championed vaccination, Benjamin Jesty, a farmer, had also become aware of the protection from smallpox that an earlier cowpox infection provided. Based on this knowledge, Jesty inoculated his wife and two sons with fluid from a cowpox lesion on one of his cows in 1774. This ultimately turned out to be a safer approach than the Turkish variolation method that involved introducing a small quantity of infective smallpox material into a skin incision, with a resultant 2% mortality. The credit for sheep anthrax vaccine goes to Louis Pasteur, who made a public demonstration of his anthrax vaccination methodology in 1881 by inoculating 25 sheep, with another 25 sheep retained as controls. When challenged with anthrax spores, 24 of the 25 vaccinated sheep survived compared with only 2 of 25 survivors in the control group. However, Pasteur did not give credit to Henri Toussaint, who developed the method to inactivate anthrax bacteria using phenol. Later, Pasteur developed a killed vaccine for rabies from air-dried spinal cords of infected rabbits. He successfully vaccinated a 9-year-old boy, Joseph Meister, bitten by a rabid dog in 1885, and Meister survived. This was the first therapeutic vaccination, because Meister was vaccinated after exposure to rabies.

Starting with serendipity and observation in the late 1700s, vaccine methodologies evolved into empiric approaches involving isolation, inactivation, and the use of killed microbes in the late 19th and first half of the 20th centuries. For diphtheria and tetanus, toxins were identified as the cause of the disease, and antiserum made against toxins in horses was used in passive vaccination. From 1880 to 1950, vaccines were developed successfully to tackle rabies, diphtheria, tetanus, and polio. The bacillus Calmette-Guérin (BCG) vaccine for tuberculosis was also developed during this period.

The second half of the 20th century saw two new successful vaccine development approaches: recombinant DNA technology and glycoconjugation or polysaccharide-protein conjugation. By 1980, the recombinant method yielded two effective vaccines, one for HBV and the other for HPV. By 1990, the polysaccharide-protein conjugation method enabled the development of the meningococcal ACWY (MenACWY), Haemophilus influenzae type b (Hib), and pneumonia vaccines. These newer vaccines are also referred to as subunit vaccines because they contain only parts of the pathogen but are capable of generating an adequate immune response after vaccination. In the first decade of the 21st century, genome-derived reverse vaccinology approaches using bioinformatics methods were employed to develop the meningococcal B (MenB) vaccine. Fig. 18.4 illustrates the vaccination milestones.

Public Health Impact of Vaccines

The 20th century saw the development of new and effective vaccines for many infectious diseases, resulting in a dramatic reduction in mortality and morbidity from the onslaught of these diseases. Just in the 20th century alone, smallpox killed more than 500 million people before the worldwide eradication strategy of the disease succeeded, and smallpox was eliminated as a disease in 1980. Although effective vaccines have been developed for influenza, approximately 30,000 people on average succumb to the complications resulting from influenza in the United States alone each year. This translates to approximately half a million deaths globally every year from influenza. Measles causes more than 100,000 deaths worldwide in spite of the availability of an effective vaccine from the 1960s. The reasons for the failure to control outbreaks of diseases in many countries of the world, even when effective vaccines are available, can be traced to economic disparities, widespread ignorance among the populace, lack of political will in the countries’ leadership, and inadequate allocation of resources for public health. However, a substantial increase in the life expectancy of children and by extension in the whole populace was observed globally in the second half of the 20th century as a result of the impact of vaccination and immunization campaigns led by the World Health Organization (WHO) and the respective public health authorities of various countries.

The dramatic reduction in mortality and morbidity of various infectious diseases observed in the last century in the United States clearly illustrates the significant impact of vaccines in the prevention and control of various infectious diseases. By the end of the 20th century, the percentage reduction in morbidity for smallpox, diphtheria, pertussis, tetanus, paralytic polio, measles, mumps, and rubella varied between 99.3% and 100% (see Table 18.1 for additional details). Paralytic polio is on the verge of global eradication, having been eliminated from the developed world and most developing countries. However, there were isolated reports of paralytic polio during a period of 19 months (January 2019 to July 2020) in 5 countries of Asia (Afghanistan, China, Myanmar, Pakistan, Philippines) and 14 countries of Africa. Among these countries, only Afghanistan and Pakistan have documented paralytic polio caused by wild-type poliovirus. Paralytic polio cases in the other countries are oral polio vaccine–associated paralytic poliomyelitis resulting from circulating vaccine-derived poliovirus.

Types of Vaccines

As noted earlier, the field of vaccinology started with live attenuated and inactivated vaccines. During the last part of the 20th century, and more so in this century, the focus has shifted to subunit vaccines particularly for tackling emergent viral diseases. These subunit vaccines typically consist of surface proteins that can induce a significant immune response, and they could also be conjugated with polysaccharides. Subunit vaccines also can be engineered with DNA or RNA segments that encode for the immunogenic proteins. These vaccines are also referred to as recombinant vaccines. Because the recombinant vaccines consist of specific immunogens, they typically elicit a better immune response than inactivated vaccines. Recombinant vaccines are also considered safe when compared with live attenuated vaccines because there is no danger of virulence. The vaccine types are illustrated in Fig. 18.5 .

Therapeutic Vaccines

Therapeutic vaccination involves the administration of a vaccine to manage or treat a preexisting disease or clinical condition. The general goal here is to target noninfectious diseases such as cancer, Parkinson disease, Alzheimer disease, multiple sclerosis, arthritis, or conditions such as obesity, high blood pressure, and drug addictions. The challenge here is to critically understand the disease pathogenesis and pathological conditions and come up with suitable targets for vaccination. Note that in the case of noninfectious diseases, we are dealing with host proteins as opposed to pathogen-derived proteins as targets, and this can cause problems with immune targeting. The recognition of specific conformational forms in the pathological processes associated with the disease is a key step in the development of effective therapeutic vaccines. ^, Identification of circulating cytotoxic T cells specific to tumor antigens indicates that induction of an immunogenic response to mutated tumor host proteins is feasible.

Therapeutic vaccines are broadly categorized into cancer vaccines and noninfectious noncancer (NINC) vaccines. Current cancer vaccines include personalized tumor immunotherapy, prostate cancer vaccine, and the use of BCG vaccine for bladder cancer. NINC vaccines are an area of intense investigation, with vaccines for addiction, high blood pressure, and obesity, currently in exploratory stages (see Fig. 18.6 for more details.)

The first use of therapeutic vaccination was to address the infectious disease rabies. The vaccine is still in use effectively to this day for this purpose with excellent efficacy as long as it is used early enough after infection. There may be a role for therapeutic vaccination in patients with COVID-19 who continue to have symptoms past the initial 4 weeks of illness.

Vaccines, Immunity, and Age

Age exerts a significant influence on the immune system. Generating immunological response by vaccination is easier in the young, whereas immune protection is quite challenging in older people. Low efficacy of seasonal influenza vaccine in the elderly has been well documented. ^, Immune competence decreases with increasing age, which is termed immunosenescence. This can result from changes at multiple levels of the immune system over time, such as reduced lymphopoiesis in the bone marrow and thymus atrophy. These in turn result in a lower output of native T lymphocytes. Likewise, T-cell receptors and B-cell receptors are also negatively affected by aging. This implies that a conventional vaccine based on young adult responses may not be highly effective in older adults. ^, Supplementation of vaccination with immunotherapy by an infusion of neutralizing monoclonal antibodies might be needed in the elderly for enhanced protection.

Vaccine Protection Mechanisms

It is critical to understand what vaccines can and cannot do. Vaccines do not prevent pathogen entry or transient pathogen growth. Stimulating the host immune response by activating innate and adaptive immune mechanisms, vaccines can block pathogens from establishing a firm foothold by inhibiting the growth, development, and unchecked replication of these organisms. They can prevent the occurrence of clinical manifestations of disease or reduce the severity and complications resulting from infections. The goal of vaccination is to induce adaptive immunity that is specific for vaccine antigens. This facilitates the development of persistent antibodies, and memory B-cell and T-cell responses. This cascade of events protects the vaccinated individual during later contact with the virulent pathogen. The vaccine components engage the innate immune mechanism to induce protective adaptive immune responses.

Vaccine Development Process

Creating an effective and safe vaccine involves the successful completion of five critical stages: exploratory, preclinical, clinical trials, US Food and Drug Administration (FDA) review and approval, and, finally, manufacturing the required number of doses. These stages are usually sequential, and successful completion of a specific stage is necessary to move forward to the next stage. The COVID-19 pandemic has seen some changes to this paradigm with production often occurring before FDA review or approval. The exploratory stage incorporates in silico medicinal chemistry and biological experimentation, which leads to the preclinical stage, which typically involves testing for safety and efficacy on laboratory animals and possibility even primates. Successful completion of these two stages moves the process forward to the most important stage, the clinical trials stage, which will be discussed in some detail. Fig. 18.7 illustrates these five stages of the vaccine development process. The figure also shows the accelerated timeline with overlapping stages (stages 3, 4, and 5) for possible emergency use authorization in the case of pandemics.