Antiviral Vaccines: Challenges and Advances

1 Introduction

Vaccination is the most effective means of preventing and controlling viral infections. The eradication of smallpox and the significant progress made toward polio eradication are clear examples of the great impact of antiviral vaccines. However, viral infections remain a major public health threat and a significant cause of death. Most of the antiviral vaccines introduced over the past century were empirically developed. Poliomyelitis, measles, mumps, and rubella are examples of diseases that are now largely controlled thanks to these empirically developed vaccines.

The common factor among our most effective antiviral vaccines is that they were developed to mimic our natural immune response to the pathogen. For example, a single episode of measles confers lifelong immunity in the survivors. Hence, what we needed to do is induce a similar immune response. It is when we have to do better than “mother nature” that we have been facing substantial challenges in developing successful vaccines. For example, the immune response against viruses such as HIV, influenza, and respiratory syncytial virus (RSV) is either inadequate or outpaced by the pathogen’s evolution. And while developing a broadly protective vaccine against such pathogens has been a colossal task, it is not impossible and similar missions have been successfully accomplished as in the case of anti-HBV and anti-HPV vaccines.

There is a growing list of emerging and reemerging viral infections against which an effective vaccine is yet to be developed. Recent technological advances in the areas of immunogen design, single cell transcriptomics, systems biology, gene delivery, epigenetics, nanoparticles, and adjuvants expanded our understanding of how vaccines work and provide potentially new platforms that could be harnessed to develop vaccines against challenging and emerging viral pathogens.

2 Types of currently licensed antiviral vaccines

Live viral vaccines . Live virus vaccines are prepared from viral strains that have been attenuated, but retain their ability to replicate in the human host and thus their ability to induce protective immune responses. Out of the 15 viruses against which antiviral vaccines are currently licensed in the United States, nine are live attenuated ( Table 15.1 ). There are several immunological advantages for utilizing the live attenuated antiviral vaccine platform; (1) the replication of the attenuated vaccine strains in host cells allows for the potential activation of antigen-specific CD8 ⁺ T-cell responses; (2) the potential of eliciting a mucosal immune response (eg, IgA), where the portal of entry for many viruses resides. Several methods have been used to attenuate virus strains in order to be safely used as human vaccines. One method depended on the use of viral strains that are specific to a different host as vaccine strain. The oldest example of such strategy is the use of cowpox virus to vaccinate humans against smallpox. Another strategy relied on attenuation of the virus by passaging it in unnatural host or cells. Examples of this approach are the development of 17D, the yellow fever vaccine strain and polioviruses. Introducing the virus via unnatural route is a strategy used to develop adenovirus Types 4 and 7 vaccine, which is given orally. Finally, generation of temperature sensitive mutants such as the live attenuated influenza vaccines.

Table 15.1

List of the Various Characteristics of Currently Licensed Antiviral Vaccines in the United States ^a

Virus	Number of serotypes included per disease	Platform	Adjuvant	Route of administration	Test used to measure the correlate of protection	Trade name
Adenovirus	2 (Types 4 and 7)	Live attenuated	No	Oral	Neutralization	No trade name, Barr Labs
Hepatitis A	1	Inactivated	Aluminum salts	Intramuscular	ELISA	Havrix, GSK
Hepatitis A	1	Inactivated				VAQTA, Merck
Hepatitis A	1	Inactivated				Twinrix, GSK
Hepatitis B	1	VLP				Twinrix, GSK
Hepatitis B	1	VLP	Aluminum salts	Intramuscular		Recombivax HB, Merck
Hepatitis B	1	VLP	Aluminum salts	Intramuscular		Engerix-B, GSK
Papillomavirus	4 (Types 6, 11, 16, 18)	VLP	Aluminum salts	Intramuscular		Gardasil, Merck
	9		Aluminum salts			Gardasil 9, Merck
	2 (Types 16 and 18)		AS04			Cervarix, GSK
Influenza	1 (2009 pH1N1)	Split	No	Intramuscular	HAI ^b	No trade name, CSL
		Live attenuated	No	Intranasal		No trade name, MedImmune
		Split	No	Intramuscular		No trade name, ID Biomedical
		Subunit	No			No trade name, Novartis
		Split	No			No trade name, Sanofi Pasteur
	1 (H5N1)	Split	No			No trade name, Sanofi Pasteur
	1 (H5N1)	Split	AS03			No trade name, ID Biomedical
	3 (H1N1, H3N2, and type B)	Subunit	MF59			FLUAD, Novartis
		Split	No			Afluria, CSL
		Split	No			FluLaval, ID Biomedical
		Live attenuated	No	Intranasal		FluMist, MedImmune
		Split	No	Intramuscular		Fluarix, GSK
		Subunit	No	Intramuscular		Fluvirin, Novartis
		Subunit	No	Intramuscular		Agriflu, Novartis
		Split	No	Intramuscular or Intradermal		Fluzone, Sanofi Pasteur
		Subunit	No	Intramuscular		Flucelvax, Novartis
		Recombinant	No	Intramuscular		Flublok, Protein Sciences
	4 (H1N1, H3N2, and two type B strains)	Live attenuated	No	Intranasal		FluMist Quadrivalent, MedImmune
		Split	No	Intramuscular		Fluarix Quadrivalent, GSK
		Split	No	Intramuscular		Fluzone Quadrivalent, Sanofi Pasteur
		Split	No	Intramuscular		FluLaval Quadrivalent, ID Biomedical
Japanese Encephalitis	1	Inactivated	Aluminum salts	Intramuscular	Neutralization	Ixiaro, Intercell Biomed
Japanese Encephalitis	1	Inactivated	No	Subcutaneous	Neutralization	JE-Vax, BIKEN-Osaka
Measles and mumps ^c	1	Live attenuated	No	Subcutaneous	Neutralization	M-M-Vax, Merck
Measles, mumps, and rubella	1	Live attenuated	No	Subcutaneous	Neutralization (measles and mumps) Immunoprecipitation (rubella)	M-M-R II, Merck
Measles, mumps, rubella, and varicella	1	Live attenuated	No	Subcutaneous	Neutralization (measles and mumps) Immunoprecipitation (rubella) FAMA gp ELISA (varicella)	ProQuad, Merck
Poliovirus	3 (Types 1, 2, 3)	Inactivated	No	Intramuscular or Subcutaneous	Neutralization	IPOL, Sanofi Pasteur
Rabies	1	Inactivated	No	Intramuscular		Imovax, Sanofi Pasteur
Rabies	1	Inactivated	No	Intramuscular		RabAvert, Novartis
Rotavirus	1	Live attenuated	No	Oral	Serum IgA	ROTARIX, GSK
Rotavirus	5 [G1, G2, G3, G4, and P1A(8)]	Live attenuated	No	Oral	Serum IgA	Rotateq, Merck
Smallpox	1	Live attenuated	No	Percutaneous	Neutralization	ACAM2000, Sanofi Pasteur
Varicella	1	Live attenuated	No	Subcutaneous	FAMA gp ELISA	Varivax, Merck
Yellow fever	1	Live attenuated	No	Subcutaneous	Neutralization	YF-Vax, Sanofi Pasteur
Zoster	1	Live attenuated	No	Subcutaneous	CD4 T cell Lymphoproliferation	Zostavax, Merck

a Vaccines that have been licensed, but their production has been discontinued are not included.

b HAI stands for hemagglutination inhibition assay.

c Measles, mumps, and rubella are also licensed to be used in combination with other antibacterial and antipoliovirus vaccines under different trade names that are not included in this table.

2.
Inactivated whole viral vaccines . Whole inactivated virus preparations are prepared by simply inactivating viral particles by heat, UV irradiation or by special chemical treatments. Formalin and beta-propiolactone are the most commonly used chemicals for this purpose. Vaccines against polioviruses and influenza were among the first to be prepared using this strategy. Immunogenicity of these viral preparations is usually robust as they contain multiple pathogen-associated molecular patterns (PAMPs) that could engage several of the host innate immune receptors such as the toll-like receptors (TLRs). For polio, an incident of incomplete inactivation of the vaccine preparation resulted in an outbreak of paralytic poliomyelitis in the United States, the so-called “Cutter Incident.” Hence, safety of such preparations has always been a concern.
3.
Subunit vaccines . Due to the increased risk of reactogenicity associated with whole inactivated virus vaccine preparations, purified preparations that contain the main targets of protective immune responses were developed. Subunit vaccines that contain the surface glycoproteins of influenza and hepatitis B viruses are currently licensed ( Table 15.1 ). Subunit vaccines show an improved reactogenicity profile compared to whole inactivated virus preparations, but this is usually at the expense of the immunogenicity of the vaccine. When administered with adjuvants, immune responses to these vaccines can be significantly enhanced.
4.
Recombinant viral proteins . The advance in methods of protein manufacturing made it possible to express desired viral proteins on a large scale to be used as vaccine antigens. Bacterial, yeast, insect, and mammalian cell lines have been used for this purpose. A recombinant vaccine that contains the main surface glycoprotein of influenza viruses, the hemagglutinin or HA, Flublok, has recently been licensed in the United States ( Table 15.1 ). As discussed later in the chapter, some recombinant viral proteins such as the surface antigen of hepatitis B viruses tend to form virus-like particles upon expression.
5.
Virus-like particles (VLPs) . VLPs are multimeric structures assembled from viral structural proteins. They often display viral surface proteins in a high-density repetitive manner on their surface, which may play a role in the enhanced immunogenicity observed with this kind of vaccines compared to recombinant viral proteins. In 1986, the first antiviral VLP vaccine (against hepatitis B) had been licensed. The vaccine is based on the hepatitis B surface antigen or HBsAg, which upon expression in yeast forms spherical VLPs that are then adsorbed onto alum as adjuvant. Recently, another antiviral VLP vaccine against human papillomavirus has been licensed.

3 How antiviral vaccines mediate protection?

Viral infections can be broadly classified into three main categories depending on the nature of the infection:

1.
Acute infections caused by antigenically stable viruses. Infection with- or vaccination against such viruses provides a lifelong immunity to clinical reinfection. Examples of such viruses include smallpox, yellow fever, measles, mumps, rubella, and polio. Developing effective vaccines against these viruses has been relatively a straightforward process.
2.
Acute infections caused by rapidly mutating viruses. The immunity acquired against such viruses through infection or vaccination is usually short-lived because of the antigenic changes, and recurrent immunization is often required. The clearest example for such viruses is influenza.
3.
Chronic infections caused by rapidly mutating viruses. HIV and HCV are prime examples for such viruses. Developing vaccines against such viruses have proved to be a very daunting task.

Two main effector arms of the adaptive immune response that are induced by antiviral vaccines mediate protection against viral infections: antibodies and T cells. While we will briefly discuss these two arms later in the chapter, it is important to understand that other immune effectors such as cytokines secreted by innate immune cells activated by the vaccine itself or by coadministered adjuvants could also directly contribute to controlling the viral burden. Also, the initial innate immune recognition of the vaccines/adjuvants is essential not only for triggering the adaptive immune responses, but also for determining the quality and duration of such responses.

3.1 Antibodies

Given the speed with which most viruses replicate, possessing protective levels of preformed antibodies is the best strategy to protect against most viral infections. Therefore, a major immunological goal for antiviral vaccines is to elicit high and durable levels of antigen-specific antibodies. Preferably these antibodies are induced at the portal of virus entry. To date, all human vaccines that have shown considerable success in combating viral infections depend on antibodies as the primary mediators of protection. The process of generating these antibodies starts when a vaccine antigen encounters and binds to its specific B cell. In the presence of cognate CD4 T-cell help, these vaccine specific B cells start to expand. Some of the activated B cells differentiate into plasmablasts whose function is to secrete an early protective wave of antigen-specific antibodies. In a primary vaccination, those early antibodies are mostly IgM and bind to the vaccine antigen with a relatively low affinity. A subset of the activated B cells will continue expanding forming specially organized structures in the secondary lymph nodes known as germinal centers (GCs). GCs are where vaccine-specific B cells with the highest antigen binding affinity are preferentially selected and also where the majority of antibody isotype-switching from IgM to IgG and IgA occurs.

Antibodies can protect against viral infections via several ways:

1.
When induced to sufficient levels, antibodies prevent infection by blocking the binding of viruses to their receptors on host cells. These are called “neutralizing” antibodies, and their target epitopes lie primarily within the surface glycoproteins of enveloped viruses or the capsid proteins of nonenveloped ones. The target epitopes of neutralizing antibodies are usually conformational.
2.
Opsonization and phagocytosis of viral particles by neutralizing and nonneutralizing antibodies that bind to the surface of viral particles.
3.
Lysing infected cells that express viral antigens on their surface via the complement pathway or through antibody-dependent cellular cytotoxicity (ADCC). For ADCC, cells mediating the lysis of infected cells such as natural killer (NK) cells recognize the antibody labeling infected cells via Fc receptors.

The cells responsible for the maintenance of antigen-specific serum antibody levels following vaccination and infection are long-lived plasma cells. These cells are generated during the germinal center reaction and reside mainly in the bone marrow.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here